Trial Outcomes & Findings for Nintedanib and Weekly Docetaxel in Lung Adenocarcinoma (NCT NCT02668393)

Last Updated: 2021-01-29

Results Overview

Maximum tolerated dose (MTD) of nintedanib administered in combination with docetaxel. The MTD was defined as the highest dose combination studied for which the incidence of DLTs was no more than 1 out of 6 subjects experiencing a DLT during the first treatment cycle i.e. the incidence of DLTs was no more than 17%. In case dose escalation reached dose level 3 (200 mg bid nintedanib administered without interruption on days of docetaxel infusion) and no more than 1 out of 6 subjects experienced a DLT during the first 28-day cycle at this dose level, dose level 3 was considered the MTD.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

14 participants

Primary outcome timeframe

First treatment cycle, the first 28 days following the start of trial medication.

Results posted on

2021-01-29

Participant Flow

This study is an open-label Phase I of oral nintedanib plus weekly docetaxel therapy in subjects with locally advanced or metastatic lung adenocarcinoma after failure of platinum-based first-line chemotherapy.

All subjects who signed informed consent were screened for eligibility prior to participation in the trial. Subjects were assigned to trial drug if they met all inclusion criteria and none of the exclusion criteria. Subjects attended a specialist site in oncology.

Participant milestones

Participant milestones
Measure	150 mg Nintedanib + Docetaxel In a treatment cycle of 28 days, 150 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 100 mg twice a day, a second dose reduction was not allowed.	200 mg Nintedanib + Docetaxel In a treatment cycle of 28 days, 200 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 150 mg twice a day with a possible second dose reduction to 100 mg twice a day.
Overall Study STARTED	7	7
Overall Study COMPLETED	0	1
Overall Study NOT COMPLETED	7	6

Reasons for withdrawal

Reasons for withdrawal
Measure	150 mg Nintedanib + Docetaxel In a treatment cycle of 28 days, 150 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 100 mg twice a day, a second dose reduction was not allowed.	200 mg Nintedanib + Docetaxel In a treatment cycle of 28 days, 200 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 150 mg twice a day with a possible second dose reduction to 100 mg twice a day.
Overall Study Progressive disease	6	3
Overall Study Adverse Event	0	2
Overall Study Withdrawal from the trial	0	1
Overall Study Lack of benefit and side effects	1	0

Baseline Characteristics

Nintedanib and Weekly Docetaxel in Lung Adenocarcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	150 mg Nintedanib + Docetaxel n=7 Participants In a treatment cycle of 28 days, 150 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 100 mg twice a day, a second dose reduction was not allowed.	200 mg Nintedanib + Docetaxel n=7 Participants In a treatment cycle of 28 days, 200 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 150 mg twice a day with a possible second dose reduction to 100 mg twice a day.	Total n=14 Participants Total of all reporting groups
Age, Continuous	67.0 years STANDARD_DEVIATION 7.6 • n=5 Participants	60.3 years STANDARD_DEVIATION 7.8 • n=7 Participants	63.6 years STANDARD_DEVIATION 8.2 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Race/Ethnicity, Customized White	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Race/Ethnicity, Customized Not reported due to local law restrictions	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants

PRIMARY outcome

Timeframe: First treatment cycle, the first 28 days following the start of trial medication.

Population: Maximum tolerated dose (MTD) Evaluation Set: All subjects who received at least one dose of study medication and were evaluable for MTD determination.

Outcome measures

Outcome measures
Measure	Nintedanib + Docetaxel n=12 Participants Comprises all dose cohorts during the dose escalation phase. In a treatment cycle of 28 days, 150 milligram (mg) nintedanib was taken orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression.	200 mg Nintedanib + Docetaxel In a treatment cycle of 28 days, 200 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 150 mg twice a day with a possible second dose reduction to 100 mg twice a day.
Maximum Tolerated Dose (MTD) of Nintedanib Administered in Combination With Docetaxel	NA milligram Maximum tolerated dose was not reached as recruitment of participants into the dose escalation part was not fully completed due to premature discontinuation of the study.	—

PRIMARY outcome

Timeframe: First treatment cycle, the first 28 days following the start of trial medication.

Population: Maximum tolerated dose (MTD) Evaluation Set: All subjects who received at least one dose of study medication and were evaluable for MTD determination.

Number of participants with DLT occurring during the first treatment cycle. DLT was defined as any of the following adverse events related to nintedanib: * Non-haematological drug-related Common Terminology Criteria for AEs (CTCAE) grade 3 or greater * diarrhoea CTCAE grade 2 for \>7 days despite supportive care * nausea CTCAE grade 3 or greater despite supportive care * vomiting CTCAE grade 2 or greater despite supportive care * increase in Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) to CTCAE grade 3 or greater * A increase in ALT and/or AST to CTCAE grade 2 or greater in conjunction with * total bilirubin increase of CTCAE grade 1 or greater * Platelets \<50 000/mm3 with bleeding (CTCAE ≥3) * neutropenia of any grade or duration accompanied by fever \>38.5°C * neutropenia grade 4 without fever of \>7 days duration * Inability to resume nintedanib dosing within 21 days after stopping due to toxicity.

Outcome measures

Outcome measures
Measure	Nintedanib + Docetaxel n=6 Participants Comprises all dose cohorts during the dose escalation phase. In a treatment cycle of 28 days, 150 milligram (mg) nintedanib was taken orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression.	200 mg Nintedanib + Docetaxel n=6 Participants In a treatment cycle of 28 days, 200 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 150 mg twice a day with a possible second dose reduction to 100 mg twice a day.
Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle	1 Participants	1 Participants

Adverse Events

150 mg Nintedanib + Docetaxel

Serious events: 3 serious events

Other events: 6 other events

Deaths: 0 deaths

200 mg Nintedanib + Docetaxel

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	150 mg Nintedanib + Docetaxel n=7 participants at risk In a treatment cycle of 28 days, 150 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 100 mg twice a day, a second dose reduction was not allowed.	200 mg Nintedanib + Docetaxel n=7 participants at risk In a treatment cycle of 28 days, 200 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 150 mg twice a day with a possible second dose reduction to 100 mg twice a day.
Gastrointestinal disorders Nausea	14.3% 1/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.	0.00% 0/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.
General disorders General physical health deterioration	0.00% 0/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.	14.3% 1/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.
Infections and infestations Empyema	0.00% 0/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.	14.3% 1/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm progression	14.3% 1/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.	14.3% 1/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.
Respiratory, thoracic and mediastinal disorders Cough	14.3% 1/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.	0.00% 0/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.
Respiratory, thoracic and mediastinal disorders Dyspnoea	28.6% 2/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.	0.00% 0/7 • From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days. Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.

Other adverse events

Additional Information

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Boehringer Ingelheim

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Email: [email protected]

Results disclosure agreements

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