Trial Exploring Afatinib (BIBW 2992) + Paclitaxel (Part A), Afatinib + Paclitaxel + Bevacizumab (Part B), Afatinib + Carboplatin (Part C) and Afatinib+ Paclitaxel +Carboplatin(Part D) in Patients With Advanced Solid Tumours

Sponsor

Boehringer Ingelheim (Industry)

Overall Status

Completed

CT.gov ID

NCT00809133

Collaborator

(none)

Enrollment

Locations

Arms

93.1

Duration (Months)

41.5

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of this study is to assess the optimum dose of the following medications when they are given together:

BIBW 2992 and paclitaxel (Taxol)
BIBW 2992 and paclitaxel and bevacizumab (Avastin)
BIBW 2992 and carboplatin
BIBW 2992 and paclitaxel and carboplatin The effect of the different drug combinations will also be assessed.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms	Drug: Paclitaxel Drug: Carboplatin Drug: BIBW 2992 Drug: Paclitaxel Drug: BIBW2992 Drug: Paclitaxel Drug: Carboplatin Drug: Bevacizumab Drug: BIBW 2992 Drug: BIBW 2992	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

83 participants

Allocation:

Non-Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Open Label Trial of Continuous Dosing With BIBW 2992 Combined With Paclitaxel and BIBW 2992 Combined With Paclitaxel and Bevacizumab, BIBW 2992 Combined With Carboplatin and BIBW 2992 Combined With Paclitaxel and Carboplatin in Patients With Advanced Solid Tumours

Study Start Date :

May 1, 2007

Actual Primary Completion Date :

Feb 1, 2015

Actual Study Completion Date :

Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A BIBW2992 + Paclitaxel	Drug: BIBW 2992 Escalating dose cohorts Drug: Paclitaxel Part A and B:80mg/m2 given on Day 1, 8 and 15 of 28 Day cycle.
Experimental: Part B BIBW2992 + Paclitaxel + Bevacizumab	Drug: Paclitaxel Part A and B:80mg/m2 given on Day 1, 8 and 15 of 28 Day cycle. Drug: BIBW2992 MTD dose of part A Drug: Bevacizumab Escalating dose Cohorts - 5mg / kg, 7.5mg / kg and 10mg / kg given Day 1 and Day 15 of a 28 days cycle
Experimental: Part C BIBW2992 + Carboplatin	Drug: Carboplatin AUC6 given on day 1 of 21 day cycle Drug: BIBW 2992 Escalating dose cohorts
Experimental: Part D BIBW2992 +Paclitaxel + Carboplatin	Drug: Carboplatin AUC6 given on day 1 of 21 day cycle Drug: Paclitaxel 175mg/m2 given on Day 1 of 21 Day cycle Drug: BIBW 2992 Escalating dose cohorts

Outcome Measures

Primary Outcome Measures

Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) [Cycle 1: 21 days (part C and D) or 28 days (part A and B)]
Dose limiting toxicity (DLT) was defined as an Adverse Event (AE) or laboratory abnormality considered as related to study treatment.
Maximum Tolerated Dose (MTD) [Cycle 1: 21 days (part C and D) or 28 days (part A and B)]
The MTD of afatinib in selected combination treatments was defined as the highest dose at which no more than 1 out of 6 patients experienced DLTs during the first treatment cycle, i.e. the highest dose with a DLT incidence ≤17%. The MTD was determined separately for Afatinib in combination with Paclitaxel (part A), Afatinib in combination with Paclitaxel and Bevacizumab (part B), Afatinib and Carboplatin (part C), and Afatinib in combination with Paclitaxel and Carboplatin (part D). In part C, dose escalation was not continued beyond the dose level A40C6, due to safety and pharmacokinetic considerations and upon mutual agreement between the investigators and the sponsor. Formally, no MTD was determined, however a recommended phase II dose was determined and is presented here. 0=not maximum tolerated dose, 1=is maximum tolerated dose Note, the depicted order of treatment groups is driven by dose level, not by the actual dosing steps.

Secondary Outcome Measures

Incidence and Intensity of AEs According to the Maximum Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade [From first drug administration until the end of treatment cycle 1; 21 days (part C and D) or 28 days (part A and B)]
Incidence and Intensity of AEs (Adverse Events) graded according to the maximum CTCAE (Common Toxicity Criteria for Adverse Events) grade based on the number of patients with AEs with CTCAE Grade 1-5.
Part A: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15 [Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.]
Area under the concentration-time curve of Afatinib in plasma at steady state.
Part A: Afatinib Cmax,ss on Day 15 [Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.]
Maximum measured concentration of Afatinib in plasma at steady state.
Part A: AUC0-24: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From Zero Extrapolated to 24 Hours on Day 1 and Day 15 [Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.]
AUC0-24: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 24 hours.
Part A: Paclitaxel Cmax on Day 1 and Day 15 [Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.]
Maximum measured concentration of Paclitaxel in plasma.
Part B: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15 [Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. There were no analyzable patients for Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab.]
Area under the concentration-time curve of Afatinib in plasma at steady state.
Part B: Afatinib Cmax,ss on Day 15 [Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.]
Maximum measured concentration of Afatinib in plasma at steady state.
Part B: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours on Day 1 and Day 15 [Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.]
AUC0-24: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 24 hours.
Part B: Paclitaxel Cmax on Day 1 and Day 15 [Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.]
Maximum measured concentration of Paclitaxel in plasma.
Part B: Bevacizumab Plasma Concentration [Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.]
Bevacizumab plasma concentration after infusion of Bevacizumab 5mg/kg after end of 1st and 2nd infusion in Cycle 1.
Part C: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State in Cycle 2 [Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.]
AUCt,ss: Area under the concentration-time curve of Afatinib in plasma at steady state.
Part C: Afatinib Cmax,ss in Cycle 2 [Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.]
Maximum measured concentration of Afatinib in plasma at steady state.
Part C: Area Under the Concentration-Time Curve of Carboplatin in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours in Cycle 1 and Cycle 2 [Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00.]
AUC0-24: Area under the concentration-time curve of Carboplatin in plasma over the time interval from zero extrapolated to 24 hours.
Part C: Carboplatin Cmax in Cycle 1 and Cycle 2 [Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00]
Maximum measured concentration of Carboplatin in plasma.
Part D: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State. [Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.]
AUCt,ss: Area under the concentration-time curve of Afatinib at steady state.
Part D: Afatinib Cmax,ss [Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.]
Maximum measured concentration of Afatinib in plasma at steady state.
Part D: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From 0 Extrapolated Upto 23 Hours in Cycle 1 and Cycle 2 [Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 23:00.]
AUC0-23: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 23 hours.
Part D: Paclitaxel Cmax in Cycle 1 and 2 [Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00]
Maximum measured concentration of Paclitaxel in plasma.
Part D: Area Under the Concentration-Time Curve of Carboplatin in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours in Cycle 1 and Cycle 2 [Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00]
AUC0-24: Area under the concentration-time curve of Carboplatin in plasma over the time interval from zero extrapolated to 24 hours.
Part D: Carboplatin Cmax in Cycle 1 and 2 [Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.]
Maximum measured concentration of Carboplatin in plasma.
Objective Tumour Response (Unconfirmed) [From first drug administration until the last trial drug administration, up to 1156 days.]
Number of subjects with objective tumour response (unconfirmed). Objective Response (OR) was defined as Complete Response (CR) or Partial Response (PR).
Objective Tumour Response (Confirmed) [From first drug administration until the last trial drug administration, up to 1156 days.]
Number of subjects with confirmed objective tumour response. Objective Response (OR) was defined as Complete Response (CR) or Partial Response (PR). Objective response was to be confirmed by a second tumour assessment at least 4 weeks after the assessment of CR or PR.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Male or female patients (patients) with a histologically confirmed diagnosis of malignancy that is now advanced, non-resectable and / or metastatic.
Age 18 years old or older.
Life expectancy of at least 3 months.
Written informed consent that is consistent with ICH-GCP guidelines.
Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.
Patients must have recovered from any previous surgery.
Adequate organ function including the following:
Cardiac left ventricular function with resting ejection fraction greater than or equal to 50%
Absolute neutrophil count of greater than or equal to 1,500/microlitres; greater than 2000/microlitres for carboplatin
Platelets greater than or equal to 100,000/microlitres
Total bilirubin less than or equal to 1.5 mg/dl (<26 micromol /L, SI unit equivalent).
AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal.
Creatinine less than or equal to 1.5 mg/dl (less than or equal to 132 micromol per liter, SI unit equivalent).
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of trial participation. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of trial enrolment. Breast feeding mothers will be excluded since these agents may be toxic to infants.

Exclusion criteria:

Active infectious disease
Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol
GI tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease.
Significant cardiovascular disease (a history of congestive heart failure requiring therapy, a need for anti-arrhythmic therapy for a ventricular arrhythmia, unstable angina pectoris or myocardial infarction within 6 months prior to trial entry).
Patients who require full-dose anticoagulation.
Patients not completely recovered from any therapy-related toxicities from previous chemo-, hormone-, immuno-, or radiotherapies to CTC less than or equal to Grade 1. Prior chemotherapy is allowed if completed at least 4 weeks prior to 1st trial treatment (6 weeks for mitomycin C or nitrosoureas) and the patient has recovered from the acute toxicities of that therapy.
Patients with untreated or symptomatic brain metastases. Patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least 8 weeks, no history of cerebral oedema or bleeding in the past 8 weeks and no requirement for steroids or anti-epileptic therapy
Persistent Grade 2 or greater neurotoxicity / neuropathy from any cause.
Patients on immunosuppressant therapy or with known HIV infection.
Treatment with any of the following within 4 weeks of starting trial medication, or during the trial, is not permitted: chemo-, immuno-, radio- (small field palliative radiotherapy is allowed provided this does not represent clear disease progression), biological therapies (including trastuzumab), hormone therapy (excluding LHRH agonists in prostate cancer, or bisphosphonates), or treatment with other investigational drugs.
Participation in another clinical trial within the past 4 weeks before start of therapy or concomitantly with this trial.
Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2 inhibiting drugs within the past 4 weeks before start of therapy or concomitantly with this trial.
Patients with known or suspected hypersensitivity to any of the trial drugs, their excipients or similar compounds.
Patients unable to comply with the protocol.
Active alcohol or drug abuse.
Patients with known pre-existing interstitial lung disease

Additional exclusion criteria for patients recruited to cohorts B:

Patients with known or suspected hypersensitivity to bevacizumab, its excipients or Chinese hamster ovary cell products or other recombinant human or humanised antibodies.
Patients with brain metastases (a brain scan is not required unless the patient shows signs and symptoms of brain metastases and a brain scan is performed to rule out the presence of brain metastases).
Patients with intra-abdominal inflammation .
Major surgery within 4 weeks of starting treatment or any wound(s) deemed by the investigator to pose a significant risk to the patient in the event of delayed healing.
Prior treatment with anthracycline and/or prior radiation to the chest wall ( patients in these categories will only be entered into the study where the investigator deems the benefit to the patient to outweigh the risk).
Patients with any of the following conditions: significant hypertension, significant haemoptysis, known brian metastases, thrombotic or haemorrhagic disorders, INR greater than or equal to 1.5 abnormal PTT, therapeutic anti-coagulation, squamous non small cell lung cancer Additional exclusion criteria for patients recruited to cohorts C and D

Patients with severe myelosuppression; i.e. absolute neutrophil count less than 2000/microlitres
Patients with renal impairment (creatinine clearance less than 60ml per minute by Cockcroft-Gault equation)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1200.12.4402 Boehringer Ingelheim Investigational Site	London		United Kingdom
2	1200.12.4401 Boehringer Ingelheim Investigational Site	Sutton		United Kingdom

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Related Info

Publications

None provided.

Responsible Party:

Boehringer Ingelheim

ClinicalTrials.gov Identifier:

NCT00809133

Other Study ID Numbers:

1200.12
2006-005005-55

First Posted:

Dec 17, 2008

Last Update Posted:

Mar 14, 2016

Last Verified:

Feb 1, 2016

Additional relevant MeSH terms:

Paclitaxel

Albumin-Bound Paclitaxel

Bevacizumab

Carboplatin

Afatinib

Study Results

Participant Flow

Recruitment Details	This was a phase I open label trial of continuous dosing with BIBW 2992 (Afatinib) combined with Paclitaxel and BIBW 2992 combined with Paclitaxel and Bevacizumab, BIBW 2992 combined with Carboplatin and BIBW 2992 combined with Paclitaxel and Carboplatin in patients with advanced solid tumours.
Pre-assignment Detail	This was a dose-escalation trial, using a 3+3 rule based design. Patients were eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Period Title: Overall Study
STARTED	3	7	6	3	5	7	6	8	3	9	6	8	5	7
COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	3	7	6	3	5	7	6	8	3	9	6	8	5	7

Baseline Characteristics

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)	Total
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Total of all reporting groups
Overall Participants	3	7	6	3	5	7	6	8	3	9	6	8	5	7	83
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.3 (12.9)	53.6 (11.2)	56.2 (10.5)	46.0 (11.1)	59.0 (6.8)	52.3 (10.4)	55.0 (20.5)	56.6 (9.0)	73.3 (8.3)	54.4 (14.7)	52.0 (9.8)	53.1 (14.2)	62.4 (11.1)	64.6 (8.6)	56.3 (12.3)
Sex: Female, Male (Count of Participants)
Female	2 66.7%	3 42.9%	5 83.3%	3 100%	3 60%	4 57.1%	5 83.3%	2 25%	0 0%	4 44.4%	3 50%	7 87.5%	1 20%	2 28.6%	44 53%
Male	1 33.3%	4 57.1%	1 16.7%	0 0%	2 40%	3 42.9%	1 16.7%	6 75%	3 100%	5 55.6%	3 50%	1 12.5%	4 80%	5 71.4%	39 47%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
Description	Dose limiting toxicity (DLT) was defined as an Adverse Event (AE) or laboratory abnormality considered as related to study treatment.
Time Frame	Cycle 1: 21 days (part C and D) or 28 days (part A and B)

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	3	6	6	3	5	6	6	6	3	6	6	6	5	6
Number [Participants]	0 0%	0 0%	2 33.3%	0 0%	2 40%	2 28.6%	1 16.7%	1 12.5%	0 0%	1 11.1%	0 0%	2 25%	2 40%	2 28.6%

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD)
Description	The MTD of afatinib in selected combination treatments was defined as the highest dose at which no more than 1 out of 6 patients experienced DLTs during the first treatment cycle, i.e. the highest dose with a DLT incidence ≤17%. The MTD was determined separately for Afatinib in combination with Paclitaxel (part A), Afatinib in combination with Paclitaxel and Bevacizumab (part B), Afatinib and Carboplatin (part C), and Afatinib in combination with Paclitaxel and Carboplatin (part D). In part C, dose escalation was not continued beyond the dose level A40C6, due to safety and pharmacokinetic considerations and upon mutual agreement between the investigators and the sponsor. Formally, no MTD was determined, however a recommended phase II dose was determined and is presented here. 0=not maximum tolerated dose, 1=is maximum tolerated dose Note, the depicted order of treatment groups is driven by dose level, not by the actual dosing steps.
Time Frame	Cycle 1: 21 days (part C and D) or 28 days (part A and B)

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	3	6	6	3	5	6	6	6	3	6	6	6	5	6
Number [Units on a scale]	0	1	0	0	0	0	0	1	0	1	1	0	0	0

3. Secondary Outcome

Title	Incidence and Intensity of AEs According to the Maximum Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade
Description	Incidence and Intensity of AEs (Adverse Events) graded according to the maximum CTCAE (Common Toxicity Criteria for Adverse Events) grade based on the number of patients with AEs with CTCAE Grade 1-5.
Time Frame	From first drug administration until the end of treatment cycle 1; 21 days (part C and D) or 28 days (part A and B)

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	3	7	6	3	5	7	6	8	3	9	6	8	5	7
Grade 1	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Grade 2	2 66.7%	2 28.6%	3 50%	1 33.3%	2 40%	1 14.3%	0 0%	3 37.5%	0 0%	2 22.2%	1 16.7%	0 0%	1 20%	2 28.6%
Grade 3	0 0%	5 71.4%	3 50%	2 66.7%	2 40%	3 42.9%	6 100%	4 50%	1 33.3%	4 44.4%	3 50%	6 75%	4 80%	3 42.9%
Grade 4	1 33.3%	0 0%	0 0%	0 0%	0 0%	1 14.3%	0 0%	0 0%	1 33.3%	3 33.3%	1 16.7%	2 25%	0 0%	2 28.6%
Grade 5	0 0%	0 0%	0 0%	0 0%	1 20%	2 28.6%	0 0%	1 12.5%	1 33.3%	0 0%	1 16.7%	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Part A: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15
Description	Area under the concentration-time curve of Afatinib in plasma at steady state.
Time Frame	Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.
Measure Participants	3	6	4
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	250 (9.63)	813 (58.4)	939 (60.0)

5. Secondary Outcome

Title	Part A: Afatinib Cmax,ss on Day 15
Description	Maximum measured concentration of Afatinib in plasma at steady state.
Time Frame	Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.
Measure Participants	3	6	5
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	12.3 (15.5)	46.0 (61.9)	63.5 (74.6)

6. Secondary Outcome

Title	Part A: AUC0-24: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From Zero Extrapolated to 24 Hours on Day 1 and Day 15
Description	AUC0-24: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 24 hours.
Time Frame	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.
Measure Participants	3	6	4
Day 1 (N=3, 6, 5)	1970 (52.2)	3730 (28.5)	3260 (30.1)
Day 15 (N=3, 6, 5)	3560 (12.6)	3170 (67.7)	3950 (51.8)

7. Secondary Outcome

Title	Part A: Paclitaxel Cmax on Day 1 and Day 15
Description	Maximum measured concentration of Paclitaxel in plasma.
Time Frame	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.
Measure Participants	3	6	5
Day 1	428 (387)	2090 (37.7)	1480 (63.1)
Day 15	1880 (42.2)	1590 (82.2)	2120 (68.2)

8. Secondary Outcome

Title	Part B: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15
Description	Area under the concentration-time curve of Afatinib in plasma at steady state.
Time Frame	Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. There were no analyzable patients for Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.
Measure Participants	3	0	4	6	4
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	312 (10.3)	829 (56.3)	336 (60.1)	142 (132)

9. Secondary Outcome

Title	Part B: Afatinib Cmax,ss on Day 15
Description	Maximum measured concentration of Afatinib in plasma at steady state.
Time Frame	Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.
Measure Participants	3	4	4	6	6
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	20.4 (16.5)	21.4 (37.8)	50.4 (52.9)	22.8 (78.3)	9.75 (214)

10. Secondary Outcome

Title	Part B: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours on Day 1 and Day 15
Description	AUC0-24: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 24 hours.
Time Frame	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.
Measure Participants	3	5	4	6	5
Day 1	3760 (53.0)	3330 (20.8)	5090 (38.6)	3810 (32.9)	3540 (40.3)
Day 15	NA (NA)	NA (NA)	4060 (31.8)	5290 (45.6)	NA (NA)

11. Secondary Outcome

Title	Part B: Paclitaxel Cmax on Day 1 and Day 15
Description	Maximum measured concentration of Paclitaxel in plasma.
Time Frame	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.
Measure Participants	3	6	5	6	5
Day 1	1800 (112)	1700 (24.2)	2950 (26.6)	1920 (38.4)	1750 (63.1)
Day 15	1490 (19.4)	1550 (47.4)	1620 (39.0)	2730 (48.4)	2120 (37.3)

12. Secondary Outcome

Title	Part B: Bevacizumab Plasma Concentration
Description	Bevacizumab plasma concentration after infusion of Bevacizumab 5mg/kg after end of 1st and 2nd infusion in Cycle 1.
Time Frame	Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part B: End of 1st Infusion of Cycle 1	Part B: End of 2nd Infusion of Cycle 1
Arm/Group Description	Dose escalation of Bevacizumab administered as intravenous infusion to 5 mg/kg. Bevacizumab administered on Days 1 and 15 of a 28-day cycle.	Dose escalation of Bevacizumab administered as intravenous infusion to 5 mg/kg. Bevacizumab administered on Days 1 and 15 of a 28-day cycle.
Measure Participants	14	14
Median (Inter-Quartile Range) [μg/mL]	119 (53.0)	154 (20.8)

13. Secondary Outcome

Title	Part C: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State in Cycle 2
Description	AUCt,ss: Area under the concentration-time curve of Afatinib in plasma at steady state.
Time Frame	Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.
Measure Participants	2	3
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	511 (1.87)	465 (91.8)

14. Secondary Outcome

Title	Part C: Afatinib Cmax,ss in Cycle 2
Description	Maximum measured concentration of Afatinib in plasma at steady state.
Time Frame	Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.
Measure Participants	2	2
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	41.7 (28.0)	44.2 (9.76)

15. Secondary Outcome

Title	Part C: Area Under the Concentration-Time Curve of Carboplatin in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours in Cycle 1 and Cycle 2
Description	AUC0-24: Area under the concentration-time curve of Carboplatin in plasma over the time interval from zero extrapolated to 24 hours.
Time Frame	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.
Measure Participants	3	9
Cycle 1 (N=3, 9)	77500 (5.47)	76800 (16.9)
Cycle 2 (N=3, 6)	77600 (7.36)	75700 (23.6)

16. Secondary Outcome

Title	Part C: Carboplatin Cmax in Cycle 1 and Cycle 2
Description	Maximum measured concentration of Carboplatin in plasma.
Time Frame	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.
Measure Participants	3	9
Cycle 1 (N=3, 9)	15100 (19.3)	21100 (31.0)
Cycle 2 (N=3, 6)	15200 (18.1)	19600 (26.8)

17. Secondary Outcome

Title	Part D: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State.
Description	AUCt,ss: Area under the concentration-time curve of Afatinib at steady state.
Time Frame	Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	6	2	2	2
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	326 (60.4)	454 (61.7)	506 (14.9)	119 (0.110)

18. Secondary Outcome

Title	Part D: Afatinib Cmax,ss
Description	Maximum measured concentration of Afatinib in plasma at steady state.
Time Frame	Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	7	2	2	2
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	18.3 (52.6)	27.3 (48.4)	28.1 (4.27)	6.73 (7.99)

19. Secondary Outcome

Title	Part D: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From 0 Extrapolated Upto 23 Hours in Cycle 1 and Cycle 2
Description	AUC0-23: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 23 hours.
Time Frame	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 23:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	8	7	5	6
Cycle 1 (N=5, 7, 5, 6)	10400 (21.8)	13000 (24.9)	9220 (43.8)	10200 (19.9)
Cycle 2 (N=8, 5, 2, 4)	10700 (32.2)	14800 (9.78)	11900 (41.4)	9270 (53.2)

20. Secondary Outcome

Title	Part D: Paclitaxel Cmax in Cycle 1 and 2
Description	Maximum measured concentration of Paclitaxel in plasma.
Time Frame	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	8	7	5	6
Cycle 1 (N=5, 7, 5, 6)	3710 (23.4)	4230 (33.7)	2570 (36.6)	3020 (29.1)
Cycle 2 (N=8, 5, 2, 4)	3620 (50.9)	4850 (20.7)	3290 (52.7)	2590 (92.3)

21. Secondary Outcome

Title	Part D: Area Under the Concentration-Time Curve of Carboplatin in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours in Cycle 1 and Cycle 2
Description	AUC0-24: Area under the concentration-time curve of Carboplatin in plasma over the time interval from zero extrapolated to 24 hours.
Time Frame	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	8	7	5	7
Cycle 1 (N=5, 7, 5, 7)	69700 (12.4)	64900 (29.6)	68700 (17.2)	81000 (15.3)
Cycle 2 (N=8, 5, 2, 5)	65400 (20.9)	74800 (15.1)	72100 (27.5)	90300 (15.7)

22. Secondary Outcome

Title	Part D: Carboplatin Cmax in Cycle 1 and 2
Description	Maximum measured concentration of Carboplatin in plasma.
Time Frame	Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	8	7	5	7
Cycle 1 (N=5, 7, 5, 7)	16200 (22.9)	17900 (17.6)	15600 (28.0)	18500 (24.3)
Cycle 2 (N=8, 5, 2, 5)	17800 (15.8)	18600 (24.2)	12800 (0)	21500 (14.3)

23. Secondary Outcome

Title	Objective Tumour Response (Unconfirmed)
Description	Number of subjects with objective tumour response (unconfirmed). Objective Response (OR) was defined as Complete Response (CR) or Partial Response (PR).
Time Frame	From first drug administration until the last trial drug administration, up to 1156 days.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	3	7	6	3	5	7	6	8	3	9	6	8	5	7
Objective response: No	3 100%	3 42.9%	5 83.3%	3 100%	4 80%	5 71.4%	5 83.3%	7 87.5%	2 66.7%	7 77.8%	4 66.7%	6 75%	2 40%	6 85.7%
Objective response: Yes	0 0%	4 57.1%	1 16.7%	0 0%	1 20%	2 28.6%	1 16.7%	1 12.5%	1 33.3%	2 22.2%	2 33.3%	2 25%	3 60%	1 14.3%

24. Secondary Outcome

Title	Objective Tumour Response (Confirmed)
Description	Number of subjects with confirmed objective tumour response. Objective Response (OR) was defined as Complete Response (CR) or Partial Response (PR). Objective response was to be confirmed by a second tumour assessment at least 4 weeks after the assessment of CR or PR.
Time Frame	From first drug administration until the last trial drug administration, up to 1156 days.

Outcome Measure Data

Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)	Part A: A40P80 (Afatinib + Paclitaxel)	Part A: A50P80 (Afatinib + Paclitaxel)	Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)	Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)	Part C: A20C6 (Afatinib + Carboplatin)	Part C: A40C6 (Afatinib + Carboplatin)	Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)	Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)	Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
Measure Participants	3	7	6	3	5	7	6	8	3	9	6	8	5	7
Objective response: No	3 100%	3 42.9%	5 83.3%	3 100%	5 100%	5 71.4%	5 83.3%	8 100%	2 66.7%	7 77.8%	4 66.7%	7 87.5%	3 60%	7 100%
Objective response: Yes	0 0%	4 57.1%	1 16.7%	0 0%	0 0%	2 28.6%	1 16.7%	0 0%	1 33.3%	2 22.2%	2 33.3%	1 12.5%	2 40%	0 0%

Adverse Events

	Part A: A20P80 (Afatinib + Paclitaxel)		Part A: A40P80 (Afatinib + Paclitaxel)		Part A: A50P80 (Afatinib + Paclitaxel)		Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)		Part C: A20C6 (Afatinib + Carboplatin)		Part C: A40C6 (Afatinib + Carboplatin)		Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)		Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)		Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)		Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Time Frame	From first drug administration until 21 days (part C and D) or 28 days (part A and B) after the last trial drug administration in the last treatment cycle, up to 1184 days.
Adverse Event Reporting Description

Arm/Group Title	Part A: A20P80 (Afatinib + Paclitaxel)		Part A: A40P80 (Afatinib + Paclitaxel)		Part A: A50P80 (Afatinib + Paclitaxel)		Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)		Part C: A20C6 (Afatinib + Carboplatin)		Part C: A40C6 (Afatinib + Carboplatin)		Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)		Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)		Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)		Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
Arm/Group Description	Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.		Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.		Afatinib (film-coated tablet) 50 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8, and 15 of a 28-day cycle.		Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.		Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.		Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 5mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.		Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 7.5 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.		Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Paclitaxel 80 mg/m2 administered as intravenous infusion on Days 1, 8 and 15 and Bevacizumab 10 mg/kg administered as intravenous infusion on Days 1 and 15 of a 28-day cycle.		Afatinib (film-coated tablet) 20 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.		Afatinib (film-coated tablet) 40 mg qd (once daily) administered orally in combination with Carboplatin (intravenous infusion) at a dose targeting an AUC (Area Under the Concentration-time curve) of 6 mg/mL min (AUC6) administered on Day 1 of a 21-day cycle.		Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.		Afatinib (film-coated tablet) 30 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.		Afatinib (film-coated tablet) 40 mg qd (once daily) was administered orally in combination with Carboplatin AUC5 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.		Afatinib (film-coated tablet) 20 mg qd (once daily) was administered orally in combination with Carboplatin AUC6 (intravenous infusion) and Paclitaxel 175 mg/m2 (intravenous infusion) which were administered on Day 1 of a 21-day cycle.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part A: A20P80 (Afatinib + Paclitaxel)		Part A: A40P80 (Afatinib + Paclitaxel)		Part A: A50P80 (Afatinib + Paclitaxel)		Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)		Part C: A20C6 (Afatinib + Carboplatin)		Part C: A40C6 (Afatinib + Carboplatin)		Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)		Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)		Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)		Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		5/7 (71.4%)		3/6 (50%)		1/3 (33.3%)		4/5 (80%)		5/7 (71.4%)		6/6 (100%)		5/8 (62.5%)		3/3 (100%)		3/9 (33.3%)		3/6 (50%)		5/8 (62.5%)		4/5 (80%)		4/7 (57.1%)
Blood and lymphatic system disorders
Anaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Febrile neutropenia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Neutropenia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Thrombocytopenia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Cardiac disorders
Arrhythmia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pericardial effusion	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Tachycardia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Gastrointestinal disorders
Abdominal pain	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Diarrhoea	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		2/6 (33.3%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		1/7 (14.3%)
Diarrhoea haemorrhagic	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Dysphagia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Intestinal obstruction	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Melaena	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Nausea	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Small intestinal haemorrhage	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Vomiting	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
General disorders
Disease progression	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		2/3 (66.7%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Fatigue	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Mucosal inflammation	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pyrexia	0/3 (0%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hepatobiliary disorders
Bile duct obstruction	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Immune system disorders
Hypersensitivity	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Infections and infestations
Catheter site infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Clostridium difficile infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Device related infection	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Device related sepsis	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Diverticulitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Escherichia infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Escherichia sepsis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
H1N1 influenza	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Lobar pneumonia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Lower respiratory tract infection	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Lymphangitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Mycobacterial infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Neutropenic sepsis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Paronychia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pneumonia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pneumonia streptococcal	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Respiratory tract infection bacterial	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Sepsis	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Staphylococcal infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Urinary tract infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Injury, poisoning and procedural complications
Vascular pseudoaneurysm	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Investigations
Blood bilirubin increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Metabolism and nutrition disorders
Dehydration	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Musculoskeletal pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix cancer metastatic	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Metastases to central nervous system	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Neoplasm progression	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Non-small cell lung cancer	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Non-small cell lung cancer metastatic	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Oesophageal cancer metastatic	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pericardial effusion malignant	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Tumour haemorrhage	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Nervous system disorders
Dizziness	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Dystonia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Facial paresis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Headache	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Lethargy	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Neurological decompensation	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Partial seizures	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Presyncope	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Seizure	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Spinal cord compression	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Syncope	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Transient ischaemic attack	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Renal and urinary disorders
Hydronephrosis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Renal impairment	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Urinary retention	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Reproductive system and breast disorders
Pelvic pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pleural effusion	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Pneumothorax	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Pneumothorax spontaneous	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pulmonary embolism	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Vascular disorders
Axillary vein thrombosis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Deep vein thrombosis	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Hypotension	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Part A: A20P80 (Afatinib + Paclitaxel)		Part A: A40P80 (Afatinib + Paclitaxel)		Part A: A50P80 (Afatinib + Paclitaxel)		Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A20P80B7.5 (Afatinib + Paclitaxel + Bevacizumab)		Part B: A20P80B10 (Afatinib + Paclitaxel + Bevacizumab)		Part C: A20C6 (Afatinib + Carboplatin)		Part C: A40C6 (Afatinib + Carboplatin)		Part D: A20P175C5 ( Afatinib + Paclitaxel + Carboplatin)		Part D: A30P175C5 (Afatinib + Paclitaxel + Carboplatin)		Part D: A40P175C5 (Afatinib + Paclitaxel + Carboplatin)		Part D: A20P175C6 (Afatinib + Paclitaxel + Carboplatin)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		7/7 (100%)		6/6 (100%)		3/3 (100%)		5/5 (100%)		7/7 (100%)		6/6 (100%)		8/8 (100%)		3/3 (100%)		9/9 (100%)		6/6 (100%)		8/8 (100%)		5/5 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Anaemia	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		1/5 (20%)		1/7 (14.3%)		2/6 (33.3%)		2/8 (25%)		1/3 (33.3%)		2/9 (22.2%)		4/6 (66.7%)		2/8 (25%)		1/5 (20%)		3/7 (42.9%)
Leukopenia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		3/6 (50%)		3/8 (37.5%)		1/5 (20%)		2/7 (28.6%)
Lymph node pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Microcytic anaemia	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Neutropenia	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		2/6 (33.3%)		2/8 (25%)		0/3 (0%)		4/9 (44.4%)		5/6 (83.3%)		5/8 (62.5%)		1/5 (20%)		3/7 (42.9%)
Thrombocytopenia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		3/9 (33.3%)		2/6 (33.3%)		3/8 (37.5%)		1/5 (20%)		2/7 (28.6%)
Cardiac disorders
Bradycardia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Left ventricular dysfunction	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Palpitations	0/3 (0%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Sinus tachycardia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Tachycardia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Ventricular extrasystoles	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Ear and labyrinth disorders
Ear discomfort	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Ear haemorrhage	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Ear pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Tinnitus	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Vertigo	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Eye disorders
Episcleritis	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Eye discharge	0/3 (0%)		0/7 (0%)		2/6 (33.3%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Eye pruritus	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Glaucoma	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Lacrimation increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Vision blurred	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Visual impairment	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Abdominal distension	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Abdominal pain	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		1/3 (33.3%)		1/5 (20%)		2/7 (28.6%)		2/6 (33.3%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		2/8 (25%)		1/5 (20%)		4/7 (57.1%)
Abdominal pain upper	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Cheilitis	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Constipation	1/3 (33.3%)		2/7 (28.6%)		2/6 (33.3%)		3/3 (100%)		0/5 (0%)		3/7 (42.9%)		4/6 (66.7%)		3/8 (37.5%)		1/3 (33.3%)		2/9 (22.2%)		3/6 (50%)		4/8 (50%)		3/5 (60%)		2/7 (28.6%)
Diarrhoea	2/3 (66.7%)		7/7 (100%)		6/6 (100%)		3/3 (100%)		4/5 (80%)		6/7 (85.7%)		4/6 (66.7%)		7/8 (87.5%)		1/3 (33.3%)		6/9 (66.7%)		6/6 (100%)		6/8 (75%)		5/5 (100%)		5/7 (71.4%)
Dry mouth	0/3 (0%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		2/7 (28.6%)
Dyspepsia	1/3 (33.3%)		3/7 (42.9%)		2/6 (33.3%)		1/3 (33.3%)		2/5 (40%)		2/7 (28.6%)		1/6 (16.7%)		3/8 (37.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		2/8 (25%)		0/5 (0%)		2/7 (28.6%)
Dysphagia	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Epigastric discomfort	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Flatulence	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Gastric ulcer	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Gastritis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Gastrointestinal motility disorder	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Gastrooesophageal reflux disease	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		2/6 (33.3%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		3/8 (37.5%)		0/5 (0%)		0/7 (0%)
Gingival pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Glossodynia	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Haemorrhoidal haemorrhage	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Haemorrhoids	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Lip dry	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		1/7 (14.3%)
Lip pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Melaena	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Mouth ulceration	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Nausea	1/3 (33.3%)		3/7 (42.9%)		2/6 (33.3%)		1/3 (33.3%)		5/5 (100%)		2/7 (28.6%)		4/6 (66.7%)		5/8 (62.5%)		1/3 (33.3%)		6/9 (66.7%)		2/6 (33.3%)		3/8 (37.5%)		3/5 (60%)		3/7 (42.9%)
Odynophagia	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Proctalgia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Rectal haemorrhage	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Stomatitis	0/3 (0%)		3/7 (42.9%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		2/9 (22.2%)		3/6 (50%)		1/8 (12.5%)		3/5 (60%)		0/7 (0%)
Tongue discolouration	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Tongue ulceration	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Tooth disorder	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Toothache	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Vomiting	1/3 (33.3%)		2/7 (28.6%)		2/6 (33.3%)		1/3 (33.3%)		2/5 (40%)		1/7 (14.3%)		2/6 (33.3%)		3/8 (37.5%)		0/3 (0%)		4/9 (44.4%)		2/6 (33.3%)		4/8 (50%)		1/5 (20%)		2/7 (28.6%)
General disorders
Adverse drug reaction	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Catheter site erythema	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Catheter site inflammation	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Catheter site pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Catheter site related reaction	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Catheter site swelling	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Chest discomfort	1/3 (33.3%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		2/8 (25%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Chest pain	1/3 (33.3%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		3/9 (33.3%)		1/6 (16.7%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Chills	0/3 (0%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		2/6 (33.3%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Disease progression	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Early satiety	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Fatigue	3/3 (100%)		5/7 (71.4%)		5/6 (83.3%)		3/3 (100%)		5/5 (100%)		6/7 (85.7%)		4/6 (66.7%)		6/8 (75%)		3/3 (100%)		7/9 (77.8%)		5/6 (83.3%)		5/8 (62.5%)		5/5 (100%)		6/7 (85.7%)
Gait disturbance	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
General physical health deterioration	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Influenza like illness	0/3 (0%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Infusion site reaction	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Mucosal inflammation	1/3 (33.3%)		5/7 (71.4%)		4/6 (66.7%)		2/3 (66.7%)		2/5 (40%)		5/7 (71.4%)		2/6 (33.3%)		5/8 (62.5%)		0/3 (0%)		2/9 (22.2%)		2/6 (33.3%)		5/8 (62.5%)		3/5 (60%)		3/7 (42.9%)
Oedema	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Oedema peripheral	1/3 (33.3%)		3/7 (42.9%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		2/6 (33.3%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Pain	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Peripheral swelling	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Pyrexia	3/3 (100%)		4/7 (57.1%)		1/6 (16.7%)		1/3 (33.3%)		2/5 (40%)		0/7 (0%)		2/6 (33.3%)		1/8 (12.5%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Suprapubic pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Tenderness	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Thrombosis in device	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Ulcer	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hepatobiliary disorders
Hepatic failure	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Hyperbilirubinaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Immune system disorders
Drug hypersensitivity	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		1/7 (14.3%)
Infections and infestations
Bacteriuria	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Blister infected	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Candida infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		2/7 (28.6%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		2/8 (25%)		0/5 (0%)		0/7 (0%)
Catheter site cellulitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Cellulitis	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Conjunctivitis	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Cystitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Device related infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Diverticulitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Folliculitis	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Fungal skin infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Genital abscess	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Genital herpes	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Gingivitis	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
H1N1 influenza	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Helicobacter infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Herpes simplex	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Impetigo	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Influenza	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Klebsiella infection	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Labyrinthitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Laryngitis viral	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Localised infection	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Lower respiratory tract infection	1/3 (33.3%)		2/7 (28.6%)		1/6 (16.7%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		1/3 (33.3%)		3/9 (33.3%)		1/6 (16.7%)		2/8 (25%)		2/5 (40%)		1/7 (14.3%)
Lung infection	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Lymphangitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Nail infection	1/3 (33.3%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Nasopharyngitis	1/3 (33.3%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Omphalitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Oral candidiasis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		1/8 (12.5%)		1/3 (33.3%)		1/9 (11.1%)		0/6 (0%)		1/8 (12.5%)		1/5 (20%)		0/7 (0%)
Oral herpes	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Paronychia	1/3 (33.3%)		3/7 (42.9%)		1/6 (16.7%)		0/3 (0%)		1/5 (20%)		2/7 (28.6%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Pharyngitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pneumonia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Rash pustular	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Rhinitis	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		2/3 (66.7%)		1/5 (20%)		2/7 (28.6%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		5/9 (55.6%)		0/6 (0%)		1/8 (12.5%)		2/5 (40%)		0/7 (0%)
Sinusitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Skin infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Tooth abscess	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Tooth infection	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Upper respiratory tract infection	1/3 (33.3%)		1/7 (14.3%)		0/6 (0%)		2/3 (66.7%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Urinary tract infection	1/3 (33.3%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		3/8 (37.5%)		0/5 (0%)		0/7 (0%)
Viral infection	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Viral upper respiratory tract infection	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Injury, poisoning and procedural complications
Fall	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Infusion related reaction	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Laceration	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Overdose	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Procedural pain	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Investigations
Activated partial thromboplastin time prolonged	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Alanine aminotransferase	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Alanine aminotransferase increased	1/3 (33.3%)		2/7 (28.6%)		2/6 (33.3%)		1/3 (33.3%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		3/8 (37.5%)		1/5 (20%)		0/7 (0%)
Aspartate aminotransferase increased	1/3 (33.3%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		1/5 (20%)		0/7 (0%)
Blood albumin decreased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Blood alkaline phosphatase increased	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Blood bilirubin increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Blood calcium increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Blood creatinine increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		1/5 (20%)		1/7 (14.3%)
Blood sodium decreased	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Blood thyroid stimulating hormone increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Body temperature increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Gamma-glutamyltransferase increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		1/8 (12.5%)		1/5 (20%)		0/7 (0%)
Haemoglobin decreased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Lymphocyte count decreased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Neutrophil count decreased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Platelet count decreased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Platelet count increased	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Transaminases increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Weight decreased	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		1/3 (33.3%)		2/9 (22.2%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Weight increased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
White blood cell count decreased	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
White blood cell count increased	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/3 (66.7%)		5/7 (71.4%)		4/6 (66.7%)		0/3 (0%)		3/5 (60%)		3/7 (42.9%)		3/6 (50%)		3/8 (37.5%)		1/3 (33.3%)		4/9 (44.4%)		1/6 (16.7%)		2/8 (25%)		3/5 (60%)		4/7 (57.1%)
Dehydration	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		2/6 (33.3%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Fluid retention	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Hypercalcaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hyperglycaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Hyperkalaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		2/9 (22.2%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hypermagnesaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hypoalbuminaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hypocalcaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		2/8 (25%)		0/5 (0%)		0/7 (0%)
Hypoglycaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hypokalaemia	1/3 (33.3%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		2/5 (40%)		2/7 (28.6%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		2/9 (22.2%)		1/6 (16.7%)		1/8 (12.5%)		0/5 (0%)		2/7 (28.6%)
Hypomagnesaemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		1/9 (11.1%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		3/7 (42.9%)
Hyponatraemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Hypophosphataemia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/5 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		3/6 (50%)		5/8 (62.5%)		2/5 (40%)		3/7 (42.9%)
Back pain	0/3 (0%)		2/7 (28.6%)		0/6 (0%)		1/3 (33.3%)		1/5 (20%)		1/7 (14.3%)		0/6 (0%)		2/8 (25%)		0/3 (0%)		2/9 (22.2%)		2/6 (33.3%)		3/8 (37.5%)		1/5 (20%)		1/7 (14.3%)
Bone swelling	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Chest wall mass	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Clubbing	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Flank pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		2/8 (25%)		0/5 (0%)		0/7 (0%)
Groin pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Joint swelling	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Limb discomfort	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Muscle spasms	1/3 (33.3%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		3/8 (37.5%)		0/5 (0%)		0/7 (0%)
Muscular weakness	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Musculoskeletal chest pain	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Musculoskeletal discomfort	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Musculoskeletal pain	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		2/8 (25%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		1/7 (14.3%)
Musculoskeletal stiffness	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Myalgia	0/3 (0%)		2/7 (28.6%)		0/6 (0%)		1/3 (33.3%)		2/5 (40%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		3/6 (50%)		1/8 (12.5%)		2/5 (40%)		1/7 (14.3%)
Myopathy	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Myositis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Neck pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		2/5 (40%)		0/7 (0%)
Pain in extremity	1/3 (33.3%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		3/8 (37.5%)		0/5 (0%)		0/7 (0%)
Pain in jaw	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Spinal pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm progression	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Nervous system disorders
Ageusia	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Amnesia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Balance disorder	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Brachial plexopathy	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Dizziness	0/3 (0%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		2/7 (28.6%)		1/6 (16.7%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		2/6 (33.3%)		3/8 (37.5%)		0/5 (0%)		1/7 (14.3%)
Dysarthria	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Dysgeusia	1/3 (33.3%)		3/7 (42.9%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		1/3 (33.3%)		2/9 (22.2%)		0/6 (0%)		2/8 (25%)		1/5 (20%)		2/7 (28.6%)
Headache	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		1/3 (33.3%)		1/5 (20%)		1/7 (14.3%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		3/8 (37.5%)		2/5 (40%)		1/7 (14.3%)
Hyperaesthesia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hypoaesthesia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Lethargy	1/3 (33.3%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		2/6 (33.3%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Loss of consciousness	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Memory impairment	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		1/7 (14.3%)
Neuropathy peripheral	1/3 (33.3%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		1/5 (20%)		2/7 (28.6%)		1/6 (16.7%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		2/6 (33.3%)		4/8 (50%)		0/5 (0%)		2/7 (28.6%)
Paraesthesia	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Peripheral sensory neuropathy	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		2/6 (33.3%)		3/8 (37.5%)		0/5 (0%)		1/7 (14.3%)
Peroneal nerve palsy	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Presyncope	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Sciatica	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Sensory disturbance	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Somnolence	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Speech disorder	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		1/5 (20%)		0/7 (0%)
Tremor	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Psychiatric disorders
Agitation	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Anxiety	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Confusional state	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Depressed mood	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		2/9 (22.2%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Depression	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		2/9 (22.2%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hallucination	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Insomnia	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		2/8 (25%)		0/3 (0%)		3/9 (33.3%)		2/6 (33.3%)		3/8 (37.5%)		1/5 (20%)		1/7 (14.3%)
Mood altered	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Renal and urinary disorders
Bladder obstruction	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Dysuria	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		2/8 (25%)		0/5 (0%)		0/7 (0%)
Haematuria	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Micturition urgency	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Nocturia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		1/7 (14.3%)
Oliguria	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pollakiuria	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Polyuria	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Urinary incontinence	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Reproductive system and breast disorders
Galactostasis	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pelvic pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Vulvovaginal discomfort	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Choking sensation	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Cough	2/3 (66.7%)		4/7 (57.1%)		0/6 (0%)		1/3 (33.3%)		2/5 (40%)		3/7 (42.9%)		1/6 (16.7%)		4/8 (50%)		0/3 (0%)		2/9 (22.2%)		1/6 (16.7%)		0/8 (0%)		3/5 (60%)		2/7 (28.6%)
Dysphonia	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		2/3 (66.7%)		3/5 (60%)		0/7 (0%)		0/6 (0%)		4/8 (50%)		0/3 (0%)		2/9 (22.2%)		0/6 (0%)		2/8 (25%)		0/5 (0%)		0/7 (0%)
Dyspnoea	2/3 (66.7%)		2/7 (28.6%)		1/6 (16.7%)		3/3 (100%)		1/5 (20%)		2/7 (28.6%)		1/6 (16.7%)		1/8 (12.5%)		0/3 (0%)		2/9 (22.2%)		0/6 (0%)		3/8 (37.5%)		0/5 (0%)		2/7 (28.6%)
Dyspnoea exertional	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Epistaxis	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		2/3 (66.7%)		3/5 (60%)		3/7 (42.9%)		4/6 (66.7%)		3/8 (37.5%)		0/3 (0%)		3/9 (33.3%)		1/6 (16.7%)		3/8 (37.5%)		1/5 (20%)		3/7 (42.9%)
Haemoptysis	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		2/8 (25%)		0/5 (0%)		1/7 (14.3%)
Hiccups	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Nasal congestion	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		2/8 (25%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Nasal dryness	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Nasal inflammation	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		2/8 (25%)		0/3 (0%)		2/9 (22.2%)		3/6 (50%)		0/8 (0%)		3/5 (60%)		0/7 (0%)
Nasal obstruction	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Oropharyngeal pain	1/3 (33.3%)		3/7 (42.9%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		2/7 (28.6%)		1/6 (16.7%)		3/8 (37.5%)		0/3 (0%)		3/9 (33.3%)		1/6 (16.7%)		1/8 (12.5%)		1/5 (20%)		1/7 (14.3%)
Pharyngeal erythema	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pleural effusion	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Pleuritic pain	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Pneumothorax	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Productive cough	1/3 (33.3%)		1/7 (14.3%)		0/6 (0%)		2/3 (66.7%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		2/8 (25%)		0/5 (0%)		1/7 (14.3%)
Pulmonary haemorrhage	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Rhinalgia	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Rhinitis allergic	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Rhinorrhoea	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Sinus congestion	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Sputum discoloured	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Sputum increased	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Upper-airway cough syndrome	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		1/5 (20%)		0/7 (0%)
Wheezing	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Acne	0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Alopecia	3/3 (100%)		2/7 (28.6%)		1/6 (16.7%)		1/3 (33.3%)		3/5 (60%)		2/7 (28.6%)		4/6 (66.7%)		4/8 (50%)		0/3 (0%)		0/9 (0%)		3/6 (50%)		2/8 (25%)		3/5 (60%)		5/7 (71.4%)
Blister	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Cold sweat	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Dermatitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Dermatitis acneiform	1/3 (33.3%)		1/7 (14.3%)		2/6 (33.3%)		0/3 (0%)		0/5 (0%)		3/7 (42.9%)		1/6 (16.7%)		1/8 (12.5%)		1/3 (33.3%)		5/9 (55.6%)		3/6 (50%)		1/8 (12.5%)		1/5 (20%)		0/7 (0%)
Drug eruption	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Dry skin	2/3 (66.7%)		4/7 (57.1%)		2/6 (33.3%)		0/3 (0%)		4/5 (80%)		3/7 (42.9%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		2/9 (22.2%)		2/6 (33.3%)		3/8 (37.5%)		1/5 (20%)		3/7 (42.9%)
Ecchymosis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Erythema	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		1/5 (20%)		0/7 (0%)
Hyperhidrosis	0/3 (0%)		0/7 (0%)		0/6 (0%)		1/3 (33.3%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Intertrigo	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Nail discolouration	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		1/7 (14.3%)
Nail disorder	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Nail pitting	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Night sweats	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		1/3 (33.3%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Onycholysis	0/3 (0%)		2/7 (28.6%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pain of skin	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Palmar-plantar erythrodysaesthesia syndrome	1/3 (33.3%)		2/7 (28.6%)		2/6 (33.3%)		0/3 (0%)		2/5 (40%)		1/7 (14.3%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		2/8 (25%)		0/5 (0%)		0/7 (0%)
Petechiae	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		1/3 (33.3%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Pruritus	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		1/6 (16.7%)		1/8 (12.5%)		1/5 (20%)		0/7 (0%)
Pruritus generalised	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Rash	1/3 (33.3%)		6/7 (85.7%)		5/6 (83.3%)		3/3 (100%)		4/5 (80%)		4/7 (57.1%)		3/6 (50%)		6/8 (75%)		2/3 (66.7%)		2/9 (22.2%)		2/6 (33.3%)		6/8 (75%)		5/5 (100%)		4/7 (57.1%)
Rash erythematous	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Rash macular	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Rash maculo-papular	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Rash papular	1/3 (33.3%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Rash pruritic	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Rosacea	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Scab	0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		2/8 (25%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Skin disorder	0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Skin fissures	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		2/8 (25%)		0/5 (0%)		0/7 (0%)
Skin reaction	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		1/6 (16.7%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Swelling face	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		1/8 (12.5%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Telangiectasia	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Vascular disorders
Flushing	1/3 (33.3%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		2/7 (28.6%)
Hot flush	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		2/7 (28.6%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)
Hypertension	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		1/6 (16.7%)		1/8 (12.5%)		1/3 (33.3%)		1/9 (11.1%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Hypotension	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/5 (0%)		1/7 (14.3%)
Orthostatic hypotension	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		1/5 (20%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		0/8 (0%)		0/5 (0%)		0/7 (0%)
Thrombophlebitis	0/3 (0%)		0/7 (0%)		0/6 (0%)		0/3 (0%)		0/5 (0%)		0/7 (0%)		0/6 (0%)		0/8 (0%)		0/3 (0%)		0/9 (0%)		0/6 (0%)		1/8 (12.5%)		0/5 (0%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

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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.

Results Point of Contact

Name/Title	Boehringer Ingelheim Call Center
Organization	Boehringer Ingelheim
Phone	1800-243-0127
Email	clintriage.rdg@boehringer-ingelheim.com

Responsible Party:

Boehringer Ingelheim

ClinicalTrials.gov Identifier:

NCT00809133

Other Study ID Numbers:

1200.12
2006-005005-55

First Posted:

Dec 17, 2008

Last Update Posted:

Mar 14, 2016

Last Verified:

Feb 1, 2016

Trial Exploring Afatinib (BIBW 2992) + Paclitaxel (Part A), Afatinib + Paclitaxel + Bevacizumab (Part B), Afatinib + Carboplatin (Part C) and Afatinib+ Paclitaxel +Carboplatin(Part D) in Patients With Advanced Solid Tumours

Study Details

Study Description

Brief Summary

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion criteria:

Exclusion criteria:

Additional exclusion criteria for patients recruited to cohorts B:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

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Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

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Results Point of Contact