Nintedanib and Weekly Docetaxel in Lung Adenocarcinoma

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02668393
• Collaborator: (none)
• Enrollment: 14
• Locations: 4
• Arms: 4
• Actual Duration (Months): 44.7
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Phase I study. To determine the MTD (Maximum Tolerated Dose) of nintedanib + weekly Docetaxel in patients with locally advanced or metastatic lung adenocarcinoma after failure of platinum-based first line chemotherapy.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Phase I of Oral Nintedanib Plus Weekly Docetaxel Therapy in Patients With Locally Advanced or Metastatic Lung Adenocarcinoma After Failure of Platinum -Based First Line Chemotherapy
• Actual Study Start Date: Mar 7, 2016
• Actual Primary Completion Date: Nov 27, 2019
• Actual Study Completion Date: Nov 27, 2019

Arms and Interventions

Arm	Intervention/Treatment
Other: Level 0 Nintedanib low dose with docetaxel	Drug: Docetaxel; Drug: Nintedanib; Low Dose
Other: Level 1 Nintedanib medium dose with docetaxel	Drug: Docetaxel; Drug: Nintedanib; Medium dose
Other: Level 2 Nintedanib high dose with docetaxel	Drug: Docetaxel; Drug: Nintedanib; High dose
Other: Level 3 Nintedanib continuous high dose with docetaxel	Drug: Docetaxel; Drug: Nintedanib; Continuous high dose

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Nintedanib Administered in Combination With Docetaxel [First treatment cycle, the first 28 days following the start of trial medication.]

   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.

2. Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle [First treatment cycle, the first 28 days following the start of trial medication.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

-Patients with histologically/ cytologically confirmed locally advanced (Stage IIIB) or metastatic (Stage IV) lung adeno carcinoma 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 line is accepted. Prior immunotherapy is allowed.

• ECOG inferior or equal to 1 at screening.

• Further inclusion criteria apply

Exclusion criteria:

• Patients who have received more than one prior line of chemotherapy (i.e. second or third line chemotherapy) for advanced or metastatic NSCLC.

• Patients known to be positive for activating Epidermal Growth Factor Receptor (EGFR) mutation or patients known to be positive for ALK translocation

• Further exclusion criteria apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HOP d'Angers	Angers		France	49 933
2	HOP Jean Minjoz	Besançon		France	25030
3	Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH	Großhansdorf		Germany	22927
4	Krankenhaus Martha-Maria Halle-Dölau gGmbH	Halle/Saale		Germany	06120

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Nov 4, 2015
• Statistical Analysis Plan - Feb 21, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02668393
• Other Study ID Numbers: 1199.224; 2015-000317-52
• First Posted: Jan 29, 2016
• Last Update Posted: Jan 29, 2021
• Last Verified: Jan 1, 2021

• Additional relevant MeSH terms: Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma of Lung; Docetaxel; Nintedanib

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	150 mg Nintedanib + Docetaxel	200 mg Nintedanib + Docetaxel
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	7	7
COMPLETED	0	1
NOT COMPLETED	7	6

Baseline Characteristics

Arm/Group Title	150 mg Nintedanib + Docetaxel	200 mg Nintedanib + Docetaxel	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	7	7	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.0 (7.6)	60.3 (7.8)	63.6 (8.2)
Sex: Female, Male (Count of Participants)
Female	2 28.6%	2 28.6%	4 28.6%
Male	5 71.4%	5 71.4%	10 71.4%
Race/Ethnicity, Customized (Number) [Number]
White	5 71.4%	5 71.4%	10 71.4%
Not reported due to local law restrictions	2 28.6%	2 28.6%	4 28.6%
Race/Ethnicity, Customized (Number) [Number]
Not Hispanic or Latino	5 71.4%	5 71.4%	10 71.4%
Not reported due to local law restrictions	2 28.6%	2 28.6%	4 28.6%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Nintedanib Administered in Combination With Docetaxel
Description	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.
Time Frame	First treatment cycle, the first 28 days following the start of trial medication.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Nintedanib + Docetaxel
Arm/Group Description	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.
Measure Participants	12
Number [milligram]	NA

2. Primary Outcome

Title	Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle
Description	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.
Time Frame	First treatment cycle, the first 28 days following the start of trial medication.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib + Docetaxel	200 mg Nintedanib + Docetaxel
Arm/Group Description	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.	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.
Measure Participants	6	6
Count of Participants [Participants]	1 14.3%	1 14.3%

Adverse Events

Time Frame	From first administration of study drug till the last administration + a residual effect period (REP) of 28 days, up to 330 days.
Adverse Event Reporting Description	Treated set (TS): all subjects who received at least one dose of study medication. The TS was used for all safety and efficacy analyses.
Arm/Group Title	150 mg Nintedanib + Docetaxel		200 mg Nintedanib + Docetaxel
Arm/Group Description	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.		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.
All Cause Mortality
	150 mg Nintedanib + Docetaxel		200 mg Nintedanib + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Serious Adverse Events
	150 mg Nintedanib + Docetaxel		200 mg Nintedanib + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/7 (42.9%)		2/7 (28.6%)
Gastrointestinal disorders
Nausea	1/7 (14.3%)		0/7 (0%)
General disorders
General physical health deterioration	0/7 (0%)		1/7 (14.3%)
Infections and infestations
Empyema	0/7 (0%)		1/7 (14.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	1/7 (14.3%)		1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/7 (14.3%)		0/7 (0%)
Dyspnoea	2/7 (28.6%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	150 mg Nintedanib + Docetaxel		200 mg Nintedanib + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)		6/7 (85.7%)
Blood and lymphatic system disorders
Anaemia	3/7 (42.9%)		1/7 (14.3%)
Leukopenia	1/7 (14.3%)		0/7 (0%)
Neutropenia	1/7 (14.3%)		1/7 (14.3%)
Eye disorders
Lacrimation increased	0/7 (0%)		1/7 (14.3%)
Vision blurred	0/7 (0%)		1/7 (14.3%)
Gastrointestinal disorders
Abdominal pain upper	0/7 (0%)		1/7 (14.3%)
Abdominal rigidity	0/7 (0%)		1/7 (14.3%)
Constipation	2/7 (28.6%)		0/7 (0%)
Diarrhoea	5/7 (71.4%)		4/7 (57.1%)
Dyspepsia	1/7 (14.3%)		0/7 (0%)
Gastrooesophageal reflux disease	1/7 (14.3%)		0/7 (0%)
Haemorrhoids	0/7 (0%)		1/7 (14.3%)
Nausea	2/7 (28.6%)		3/7 (42.9%)
Rectal haemorrhage	0/7 (0%)		1/7 (14.3%)
Stomatitis	1/7 (14.3%)		1/7 (14.3%)
Vomiting	0/7 (0%)		2/7 (28.6%)
General disorders
Asthenia	2/7 (28.6%)		0/7 (0%)
Condition aggravated	1/7 (14.3%)		0/7 (0%)
Fatigue	2/7 (28.6%)		2/7 (28.6%)
Mucosal inflammation	2/7 (28.6%)		0/7 (0%)
Oedema peripheral	0/7 (0%)		1/7 (14.3%)
Pain	2/7 (28.6%)		1/7 (14.3%)
Pyrexia	1/7 (14.3%)		1/7 (14.3%)
Hepatobiliary disorders
Hepatic pain	0/7 (0%)		1/7 (14.3%)
Infections and infestations
Conjunctivitis	0/7 (0%)		1/7 (14.3%)
Nail infection	0/7 (0%)		1/7 (14.3%)
Nasopharyngitis	1/7 (14.3%)		0/7 (0%)
Investigations
Alanine aminotransferase increased	0/7 (0%)		1/7 (14.3%)
Aspartate aminotransferase increased	1/7 (14.3%)		1/7 (14.3%)
Blood bilirubin increased	1/7 (14.3%)		0/7 (0%)
Gamma-glutamyltransferase increased	1/7 (14.3%)		1/7 (14.3%)
Transaminases increased	0/7 (0%)		1/7 (14.3%)
Metabolism and nutrition disorders
Decreased appetite	2/7 (28.6%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/7 (14.3%)		0/7 (0%)
Back pain	0/7 (0%)		1/7 (14.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	1/7 (14.3%)		0/7 (0%)
Nervous system disorders
Dizziness	0/7 (0%)		2/7 (28.6%)
Dysgeusia	1/7 (14.3%)		0/7 (0%)
Headache	1/7 (14.3%)		1/7 (14.3%)
Neuropathy peripheral	1/7 (14.3%)		0/7 (0%)
Paraesthesia	0/7 (0%)		1/7 (14.3%)
Somnolence	1/7 (14.3%)		0/7 (0%)
Taste disorder	1/7 (14.3%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	3/7 (42.9%)		0/7 (0%)
Dyspnoea	2/7 (28.6%)		2/7 (28.6%)
Epistaxis	3/7 (42.9%)		1/7 (14.3%)
Pleural effusion	0/7 (0%)		1/7 (14.3%)
Skin and subcutaneous tissue disorders
Alopecia	0/7 (0%)		2/7 (28.6%)
Dry skin	0/7 (0%)		1/7 (14.3%)
Erythema	0/7 (0%)		1/7 (14.3%)
Nail discolouration	0/7 (0%)		1/7 (14.3%)
Nail disorder	2/7 (28.6%)		0/7 (0%)
Onychalgia	1/7 (14.3%)		1/7 (14.3%)
Swelling face	0/7 (0%)		1/7 (14.3%)
Vascular disorders
Capillary leak syndrome	0/7 (0%)		1/7 (14.3%)
Haematoma	0/7 (0%)		1/7 (14.3%)
Hypertension	1/7 (14.3%)		1/7 (14.3%)
Thrombophlebitis	1/7 (14.3%)		0/7 (0%)
Thrombosis	1/7 (14.3%)		0/7 (0%)

Limitations/Caveats

Recruitment was prematurely discontinued after dose level 2 (200 milligram) due to difficulties in recruiting subjects.

More Information

Certain Agreements

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

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.