Phase I Dose Escalation Study of Concomitant BIBF 1120 and BIBW 2992 in Patients With Advanced Solid Tumours.

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00998296

Enrollment

Registered

2009-10-20

Start date

2009-10-31

Completion date

2014-07-31

Last updated

2015-08-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms

Brief summary

The primary objective of this trial is to determine the Maximum Tolerated Dose (MTD) of the combination of BIBW 2992/BIBF 1120 therapy administered concomitantly. The MTD will provide dosing recommendation for subsequent phase II trials in patients with metastatic cancer.

Interventions

DRUGBIBW 2992

EGFR inhibitor

DRUGBIBF 1120

VEGF inhibitor

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Patients with confirmed histological or cytological diagnosis of advanced solid tumours and for whom no proven therapy exists or who are not amenable to established treatments. 2. Age 18 years or older. 3. Life expectancy of at least three months. 4. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. 5. Patients previously treated and with asymptomatic brain metastases are eligible 6. Patients must have recovered from recent surgery.

Exclusion criteria

1. Active infectious disease 2. Recent surgery within the last 4 weeks prior visit 1. 3. Chronic diarrhoea or gastrointestinal tract disease resulting in an inability to take oral medication 4. History of haemorrhagic or thrombotic events 5. Significant cardiovascular diseases within 6. Current peripheral neuropathy \> Common Terminology Criteria for Adverse Events (CTCAE) grade 1 except due to trauma 7. Untreated or symptomatic brain metastases or leptomeningeal disease. 8. Treatment with an Epidermal growth Factor-receptor (EGFR)- or Heregulin Receptor 2 (HER2) inhibiting drug or antiangiogenic drug. 9. Therapeutic anticoagulation. 10. Female patients of childbearing potential. 11. Known pre-existing interstitial lung disease

Design outcomes

Primary

Measure	Time frame	Description
Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	first treatment cycle, up to 28 days	Maximum tolerated dose (MTD) of nintedanib and afatinib based on the Percentage of participants experienced dose limiting toxicities during the dose escalation phase.

Secondary

Measure	Time frame	Description
Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	First treatment administration until cut-off date of 02Oct2014; up to 336 days	Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).
Changes in Safety Laboratory Parameters	First treatment administration until cut-off date of 02 October 2014, up to 336 days	Changes in safety laboratory Parameters reported as adverse events
Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)	Day 8, Day 15, Day 22 and Day 28	Cpre,ss,norm (Dose normalized trough plasma concentration of nintedanib at steady state) are presented for the 2 MTD treatment groups (continuous administered nintedanib at 150 mg b.i.d. concomitantly with continuously administered afatinib 30 mg q.d. or with intermittently administered afatinib 40 mg q.d.) As nintedanib is given twice daily, samples are taken at Day 8, Day 15, Day 22 and Day 28; the Pharmacokinetic (PK) parameter names will be Cpre,ss,15,norm (Day 8), Cpre,ss,29,norm (Day 15), Cpre,ss,43,norm (Day 22) and Cpre,ss,55,norm (Day 28)
Trough Plasma Concentration of Afatinib at Steady State	Day 7, Day 13, Day 15, Day 22, Day 27 and Day 28	C(pre,ss) is defined as pre-dose (trough) concentration of afatinib in plasma at steady state immediately before administration of the next dose. C24,7 corresponds to the plasma concentration at 24 hours on Day 7. C24,13 corresponds to the plasma concentration at 24 hours on Day 13. C24,27 corresponds to the plasma concentration at 24 hours on Day 27.
Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	6 weeks	The investigator evaluated whether complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) occurred in a patient. CR for target lesions: Disappearance of all target lesions. CR for non-target lesions: Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (\<10mm short axis). PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study. PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions
Disease Control (DC) During the Expansion Phase	Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)	DC is defined as the best overall response of CR, PR, stable disease (SD) and non-CR/non-PD. CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions . All lymph nodes must be non-pathological in size (\<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; SD for TL: change in the sum of diameters does not satisfy PR or PD. SD in TL, non-PD in NTL lead to overall response of SD, provided there is no appearance of new lesions.
Stable Disease for at Least 12 Weeks During the Expansion Phase	Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)	SD: Neither sufficient shrinkage to qualify for PR (Partial response) nor sufficient increase to qualify for PD(Progressive disease), taking as references the smallest sum of diameters SoD while on study. PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions.
Percentage Change in the Tumour Size From Baseline During the Expansion Phase	Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)	Percentage change in the tumour size from baseline is expressed as Number of subjects with maximum decrease from baseline in the sum of longest diameters of target lesions.
Objective Response (OR) During the Expansion Phase	Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)	OR is defined as a best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.1, CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions. All lymph nodes must be nonpathological in size (\<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below: CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; All the above scenarios should also satisfy 'No occurrence of new lesions'.

Countries

France

Participant flow

Recruitment details

Trial consisted of a dose-escalation phase (to determine the maximum tolerated dose (MTD) of treatments administered concomitantly) and an expansion phase(to assess the safety and the preliminary anti-tumour activity of the combination therapy at the previously determined MTD in patients with non-small cell lung cancer or pancreatic adenocarcinoma)

Participants by arm

Arm	Count
Nintedanib 150 mg +Afatinib 30 mg - Continuously Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the dose-escalation phase.	6
Nintedanib 150 mg +Afatinib 40 mg - Continuously Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the dose-escalation phase.	3
Nintedanib 200 mg +Afatinib 10 mg - Continuously Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 10 mg was given continuously once daily (q.d.). This is a part of the dose-escalation phase.	3
Nintedanib 200 mg +Afatinib 20 mg - Continuously Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 20 mg was given continuously once daily (q.d.). This is a part of the dose-escalation phase.	3
Nintedanib 200 mg +Afatinib 30 mg - Continuously Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the dose-escalation phase.	8
Nintedanib 200 mg +Afatinib 40 mg - Continuously Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the dose-escalation phase.	3
Nintedanib 150 mg +Afatinib 40 mg - Intermittently Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the dose-escalation phase.	7
Nintedanib 200 mg +Afatinib 30 mg - Intermittently Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given intermittently once daily (q.d.) every other week. This is a part of the dose-escalation phase.	6
Nintedanib 200 mg +Afatinib 40 mg - Intermittently Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the dose-escalation phase.	6
NSCLC Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the expansion phase which follows on the dose-escalation phase.	18
Pancreatic Adenocarcinoma Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the expansion phase which follows on the dose-escalation phase.	7
Total	70

Withdrawals & dropouts

Period	Reason	FG001	FG004	FG006	FG007	FG008	FG009	FG010
Overall Study	Dose limiting or dose reducing toxicity	0	1	0	2	2	0	0
Overall Study	Other adverse event	0	1	0	0	0	1	2
Overall Study	Progressive disease	1	0	1	0	0	14	5
Overall Study	Reason other than those specified above	0	0	0	0	0	1	0
Overall Study	Refused to continue taking trial med.	0	0	0	0	0	2	0

Baseline characteristics

Characteristic	Nintedanib 150 mg +Afatinib 30 mg - Continuously	Nintedanib 150 mg +Afatinib 40 mg - Continuously	Nintedanib 200 mg +Afatinib 10 mg - Continuously	Nintedanib 200 mg +Afatinib 20 mg - Continuously	Nintedanib 200 mg +Afatinib 30 mg - Continuously	Nintedanib 200 mg +Afatinib 40 mg - Continuously	Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Nintedanib 200 mg +Afatinib 40 mg - Intermittently	NSCLC	Pancreatic Adenocarcinoma	Total
Age, Continuous	53.7 years STANDARD_DEVIATION 8.1	51.7 years STANDARD_DEVIATION 1.5	46.7 years STANDARD_DEVIATION 4.9	53.3 years STANDARD_DEVIATION 11	51.5 years STANDARD_DEVIATION 9.7	44.3 years STANDARD_DEVIATION 8.1	64.9 years STANDARD_DEVIATION 3.5	52.2 years STANDARD_DEVIATION 6	63.3 years STANDARD_DEVIATION 10.3	58.1 years STANDARD_DEVIATION 10.9	58.1 years STANDARD_DEVIATION 6.8	56.0 years STANDARD_DEVIATION 9.7
Sex: Female, Male Female	3 Participants	1 Participants	0 Participants	1 Participants	6 Participants	2 Participants	0 Participants	4 Participants	2 Participants	11 Participants	1 Participants	31 Participants
Sex: Female, Male Male	3 Participants	2 Participants	3 Participants	2 Participants	2 Participants	1 Participants	7 Participants	2 Participants	4 Participants	7 Participants	6 Participants	39 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	6 / 6	3 / 3	3 / 3	3 / 3	8 / 8	3 / 3	7 / 7	6 / 6	6 / 6	18 / 18	6 / 7
serious Total, serious adverse events	3 / 6	3 / 3	1 / 3	0 / 3	7 / 8	3 / 3	1 / 7	1 / 6	4 / 6	7 / 18	3 / 7

Outcome results

Primary

Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities

Maximum tolerated dose (MTD) of nintedanib and afatinib based on the Percentage of participants experienced dose limiting toxicities during the dose escalation phase.

Time frame: first treatment cycle, up to 28 days

Population: TS

Arm	Measure	Group	Value (NUMBER)
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Renal failure acute	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Blood creatinine increased	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatotoxicity	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Alanine aminotransferase increased	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatocellular injury	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Diarrhoea	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Aspartate aminotransferase increased	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Dehydration	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Dehydration	33.3 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Blood creatinine increased	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatotoxicity	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Diarrhoea	33.3 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Renal failure acute	66.7 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Aspartate aminotransferase increased	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatocellular injury	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Alanine aminotransferase increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatotoxicity	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatocellular injury	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Alanine aminotransferase increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Aspartate aminotransferase increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Dehydration	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Blood creatinine increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Renal failure acute	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Diarrhoea	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Blood creatinine increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Aspartate aminotransferase increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Alanine aminotransferase increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Dehydration	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Renal failure acute	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatocellular injury	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Diarrhoea	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatotoxicity	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Blood creatinine increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatocellular injury	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Aspartate aminotransferase increased	12.5 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Dehydration	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Renal failure acute	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Alanine aminotransferase increased	12.5 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatotoxicity	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Diarrhoea	25.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatotoxicity	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Dehydration	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatocellular injury	33.3 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Alanine aminotransferase increased	33.3 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Diarrhoea	33.3 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Blood creatinine increased	33.3 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Renal failure acute	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Aspartate aminotransferase increased	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatocellular injury	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Alanine aminotransferase increased	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Aspartate aminotransferase increased	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Blood creatinine increased	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Dehydration	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Diarrhoea	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Renal failure acute	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatotoxicity	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Dehydration	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Diarrhoea	16.7 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Aspartate aminotransferase increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Blood creatinine increased	16.7 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Alanine aminotransferase increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatotoxicity	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatocellular injury	16.7 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Renal failure acute	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatocellular injury	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Dehydration	16.7 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Blood creatinine increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Renal failure acute	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Aspartate aminotransferase increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Alanine aminotransferase increased	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Hepatotoxicity	16.7 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities	Diarrhoea	0.0 percentage of participants

Secondary

Changes in Safety Laboratory Parameters

Changes in safety laboratory Parameters reported as adverse events

Time frame: First treatment administration until cut-off date of 02 October 2014, up to 336 days

Population: TS

Arm	Measure	Group	Value (NUMBER)
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	0 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood bilirubin increased	0 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine increased	1 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	0 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	1 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	0 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Troponin increased	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood bilirubin increased	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	1 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	1 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Blood bilirubin increased	1 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine increased	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	1 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	1 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	1 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	1 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Blood bilirubin increased	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine increased	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	3 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood bilirubin increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	3 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	1 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine increased	1 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	3 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	3 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine increased	1 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood bilirubin increased	1 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood bilirubin increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	4 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood creatinine increased	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	1 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	3 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	1 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood creatinine increased	1 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	2 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood bilirubin increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood bilirubin increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood creatinine increased	1 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	1 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	1 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	3 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	0 participants
NSCLC	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	0 participants
NSCLC	Changes in Safety Laboratory Parameters	Blood bilirubin increased	0 participants
NSCLC	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	1 participants
NSCLC	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
NSCLC	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	1 participants
NSCLC	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
NSCLC	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	0 participants
NSCLC	Changes in Safety Laboratory Parameters	Blood creatinine increased	1 participants
NSCLC	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants
NSCLC	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	0 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Hepatic enzymes increased	0 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Gamma-glutamyltransferase increased	0 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Blood creatinine increased	0 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Blood fibrinogen increased	0 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Alanine aminotransferase increased	1 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Troponin increased	0 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Aspartate aminotransferase increased	2 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Blood bilirubin increased	2 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Blood alkaline phosphatase increased	0 participants
Pancreatic Adenocarcinoma	Changes in Safety Laboratory Parameters	Blood creatinine phosphokinase increased	0 participants

Secondary

Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)

Cpre,ss,norm (Dose normalized trough plasma concentration of nintedanib at steady state) are presented for the 2 MTD treatment groups (continuous administered nintedanib at 150 mg b.i.d. concomitantly with continuously administered afatinib 30 mg q.d. or with intermittently administered afatinib 40 mg q.d.) As nintedanib is given twice daily, samples are taken at Day 8, Day 15, Day 22 and Day 28; the Pharmacokinetic (PK) parameter names will be Cpre,ss,15,norm (Day 8), Cpre,ss,29,norm (Day 15), Cpre,ss,43,norm (Day 22) and Cpre,ss,55,norm (Day 28)

Time frame: Day 8, Day 15, Day 22 and Day 28

Population: PKS. Only 6 patients were planned to be treated in the Nintedanib 150 mg +Afatinib 30 mg- Continuously group. Nevertheless, the patients were allowed to reduce their dose and by the way they changed the group and came in the Nintedanib 150 mg +Afatinib 30 mg- Continuously group with at the end N = 8 evaluable concentrations instead of 6 planned

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)	Cpre,ss,15,norm (N= 6, 7)	0.122 nanogram/millilitre/milligram (ng/mL/mg)	Geometric Coefficient of Variation 155
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)	Cpre,ss,29,norm (N= 6, 6)	0.0948 nanogram/millilitre/milligram (ng/mL/mg)	Geometric Coefficient of Variation 136
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)	Cpre,ss,55,norm (N= 8, NA)	0.0797 nanogram/millilitre/milligram (ng/mL/mg)	Geometric Coefficient of Variation 247
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)	Cpre,ss,43,norm (N= 5, 6)	0.112 nanogram/millilitre/milligram (ng/mL/mg)	Geometric Coefficient of Variation 125
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)	Cpre,ss,55,norm (N= 8, NA)	NA nanogram/millilitre/milligram (ng/mL/mg)	—
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)	Cpre,ss,15,norm (N= 6, 7)	0.0731 nanogram/millilitre/milligram (ng/mL/mg)	Geometric Coefficient of Variation 92.2
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)	Cpre,ss,29,norm (N= 6, 6)	0.0755 nanogram/millilitre/milligram (ng/mL/mg)	Geometric Coefficient of Variation 148
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)	Cpre,ss,43,norm (N= 5, 6)	0.0762 nanogram/millilitre/milligram (ng/mL/mg)	Geometric Coefficient of Variation 79.7

Secondary

Disease Control (DC) During the Expansion Phase

DC is defined as the best overall response of CR, PR, stable disease (SD) and non-CR/non-PD. CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions . All lymph nodes must be non-pathological in size (\<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; SD for TL: change in the sum of diameters does not satisfy PR or PD. SD in TL, non-PD in NTL lead to overall response of SD, provided there is no appearance of new lesions.

Time frame: Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)

Population: Treated set

Arm	Measure	Group	Value (NUMBER)
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Disease Control (DC) During the Expansion Phase	Yes	83.3 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Disease Control (DC) During the Expansion Phase	No	11.1 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Disease Control (DC) During the Expansion Phase	Missing	5.6 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Disease Control (DC) During the Expansion Phase	Yes	28.6 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Disease Control (DC) During the Expansion Phase	No	57.1 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Disease Control (DC) During the Expansion Phase	Missing	14.3 percentage of participants

Secondary

Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0

Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).

Time frame: First treatment administration until cut-off date of 02Oct2014; up to 336 days

Population: TS

Arm	Measure	Group	Value (NUMBER)
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	0 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	1 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	2 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	2 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	2 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	1 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	0 participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	2 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	1 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	0 participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	2 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	1 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	5 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	1 participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	1 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	1 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	2 participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	1 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	4 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	2 participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	2 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	0 participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	4 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	0 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	1 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	3 participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	2 participants
NSCLC	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	7 participants
NSCLC	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	2 participants
NSCLC	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	7 participants
NSCLC	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	0 participants
NSCLC	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	2 participants
Pancreatic Adenocarcinoma	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 1	1 participants
Pancreatic Adenocarcinoma	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 4	2 participants
Pancreatic Adenocarcinoma	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 2	2 participants
Pancreatic Adenocarcinoma	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 5	0 participants
Pancreatic Adenocarcinoma	Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0	CTCAE Grade 3	2 participants

Secondary

Objective Response (OR) During the Expansion Phase

OR is defined as a best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.1, CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions. All lymph nodes must be nonpathological in size (\<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below: CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; All the above scenarios should also satisfy 'No occurrence of new lesions'.

Time frame: Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)

Population: Treated set

Arm	Measure	Group	Value (NUMBER)
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Objective Response (OR) During the Expansion Phase	No	72.2 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Objective Response (OR) During the Expansion Phase	Yes	22.2 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Objective Response (OR) During the Expansion Phase	Missing	5.6 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Objective Response (OR) During the Expansion Phase	Yes	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Objective Response (OR) During the Expansion Phase	No	85.7 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Objective Response (OR) During the Expansion Phase	Missing	14.3 percentage of participants

Secondary

Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1

The investigator evaluated whether complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) occurred in a patient. CR for target lesions: Disappearance of all target lesions. CR for non-target lesions: Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (\<10mm short axis). PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study. PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions

Time frame: 6 weeks

Population: TS

Arm	Measure	Group	Value (NUMBER)
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	33.3 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	66.7 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	66.7 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	33.3 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	66.7 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	33.3 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 10 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	33.3 percentage of participants
Nintedanib 200 mg +Afatinib 20 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	66.7 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	28.6 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	71.4 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	100 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Continuously	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	66.7 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	33.3 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	83.3 percentage of participants
Nintedanib 200 mg +Afatinib 30 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	16.7 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	100.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Nintedanib 200 mg +Afatinib 40 mg - Intermittently	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
NSCLC	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	11.8 percentage of participants
NSCLC	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	17.6 percentage of participants
NSCLC	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	70.6 percentage of participants
NSCLC	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Pancreatic Adenocarcinoma	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Stable disease	33.3 percentage of participants
Pancreatic Adenocarcinoma	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Partial response	0.0 percentage of participants
Pancreatic Adenocarcinoma	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Complete response	0.0 percentage of participants
Pancreatic Adenocarcinoma	Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1	Progressive disease	66.6 percentage of participants

Secondary

Percentage Change in the Tumour Size From Baseline During the Expansion Phase

Percentage change in the tumour size from baseline is expressed as Number of subjects with maximum decrease from baseline in the sum of longest diameters of target lesions.

Time frame: Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)

Population: Treated set

Arm	Measure	Group	Value (NUMBER)
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Percentage Change in the Tumour Size From Baseline During the Expansion Phase	>=20%	1 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Percentage Change in the Tumour Size From Baseline During the Expansion Phase	>=0% and <20%	4 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Percentage Change in the Tumour Size From Baseline During the Expansion Phase	>-30% and <0%	6 participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Percentage Change in the Tumour Size From Baseline During the Expansion Phase	<-30%	5 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Percentage Change in the Tumour Size From Baseline During the Expansion Phase	<-30%	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Percentage Change in the Tumour Size From Baseline During the Expansion Phase	>=20%	3 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Percentage Change in the Tumour Size From Baseline During the Expansion Phase	>-30% and <0%	0 participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Percentage Change in the Tumour Size From Baseline During the Expansion Phase	>=0% and <20%	3 participants

Secondary

Stable Disease for at Least 12 Weeks During the Expansion Phase

SD: Neither sufficient shrinkage to qualify for PR (Partial response) nor sufficient increase to qualify for PD(Progressive disease), taking as references the smallest sum of diameters SoD while on study. PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions.

Time frame: Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)

Population: Treated set

Arm	Measure	Group	Value (NUMBER)
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Stable Disease for at Least 12 Weeks During the Expansion Phase	Yes	44.4 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Stable Disease for at Least 12 Weeks During the Expansion Phase	No	50.0 percentage of participants
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Stable Disease for at Least 12 Weeks During the Expansion Phase	Missing	5.6 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Stable Disease for at Least 12 Weeks During the Expansion Phase	Yes	0.0 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Stable Disease for at Least 12 Weeks During the Expansion Phase	No	85.7 percentage of participants
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Stable Disease for at Least 12 Weeks During the Expansion Phase	Missing	14.3 percentage of participants

Secondary

Trough Plasma Concentration of Afatinib at Steady State

C(pre,ss) is defined as pre-dose (trough) concentration of afatinib in plasma at steady state immediately before administration of the next dose. C24,7 corresponds to the plasma concentration at 24 hours on Day 7. C24,13 corresponds to the plasma concentration at 24 hours on Day 13. C24,27 corresponds to the plasma concentration at 24 hours on Day 27.

Time frame: Day 7, Day 13, Day 15, Day 22, Day 27 and Day 28

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	Cpre,ss,15 (N= 6, NA)	15.5 nanogram/millilitre (ng/mL)	Geometric Coefficient of Variation 62
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	C24,7 (N= NA, 6)	NA nanogram/millilitre (ng/mL)	—
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	C24,13 (N= NA, 5)	NA nanogram/millilitre (ng/mL)	—
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	Cpre,ss,22 (N= 6, NA)	19.0 nanogram/millilitre (ng/mL)	Geometric Coefficient of Variation 56.5
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	C24,27 (N= NA, 2)	NA nanogram/millilitre (ng/mL)	—
Nintedanib 150 mg +Afatinib 30 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	Cpre,ss,28 (N= 8, NA)	19.1 nanogram/millilitre (ng/mL)	Geometric Coefficient of Variation 63.3
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	C24,27 (N= NA, 2)	30.5 nanogram/millilitre (ng/mL)	Geometric Coefficient of Variation 21.9
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	C24,7 (N= NA, 6)	19.6 nanogram/millilitre (ng/mL)	Geometric Coefficient of Variation 127
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	Cpre,ss,15 (N= 6, NA)	NA nanogram/millilitre (ng/mL)	—
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	Cpre,ss,28 (N= 8, NA)	NA nanogram/millilitre (ng/mL)	—
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	C24,13 (N= NA, 5)	11.5 nanogram/millilitre (ng/mL)	Geometric Coefficient of Variation 76.4
Nintedanib 150 mg +Afatinib 40 mg - Continuously	Trough Plasma Concentration of Afatinib at Steady State	Cpre,ss,22 (N= 6, NA)	NA nanogram/millilitre (ng/mL)	—

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

Phase I Dose Escalation Study of Concomitant BIBF 1120 and BIBW 2992 in Patients With Advanced Solid Tumours.

Conditions

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities

Changes in Safety Laboratory Parameters

Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)

Disease Control (DC) During the Expansion Phase

Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0

Objective Response (OR) During the Expansion Phase

Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1

Percentage Change in the Tumour Size From Baseline During the Expansion Phase

Stable Disease for at Least 12 Weeks During the Expansion Phase

Trough Plasma Concentration of Afatinib at Steady State