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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

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ClinicalTrials.gov Identifier: NCT00809133
Recruitment Status : Completed
First Posted : December 17, 2008
Results First Posted : March 14, 2016
Last Update Posted : March 14, 2016
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Non-Randomized;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Neoplasms
Interventions Drug: Paclitaxel
Drug: Carboplatin
Drug: BIBW 2992
Drug: BIBW2992
Drug: Bevacizumab
Enrollment 83
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 Details 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)
Hide 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
Reason Not Completed
Progressive disease             2             5             5             3             4             1             3             3             3             9             5             7             5             4
Dose Limiting Toxicity (DLT)             0             0             0             0             0             1             1             1             0             0             0             0             0             2
Other adverse event             1             1             1             0             0             3             2             4             0             0             1             1             0             1
Lost to Follow-up             0             0             0             0             0             1             0             0             0             0             0             0             0             0
Consent withdrawn             0             0             0             0             1             0             0             0             0             0             0             0             0             0
Other not mentioned above             0             1             0             0             0             1             0             0             0             0             0             0             0             0
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
Hide 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 Number of Baseline Participants 3 7 6 3 5 7 6 8 3 9 6 8 5 7 83
Hide Baseline Analysis Population Description
Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3 participants 7 participants 6 participants 3 participants 5 participants 7 participants 6 participants 8 participants 3 participants 9 participants 6 participants 8 participants 5 participants 7 participants 83 participants
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  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 7 participants 6 participants 3 participants 5 participants 7 participants 6 participants 8 participants 3 participants 9 participants 6 participants 8 participants 5 participants 7 participants 83 participants
Female
2
  66.7%
3
  42.9%
5
  83.3%
3
 100.0%
3
  60.0%
4
  57.1%
5
  83.3%
2
  25.0%
0
   0.0%
4
  44.4%
3
  50.0%
7
  87.5%
1
  20.0%
2
  28.6%
44
  53.0%
Male
1
  33.3%
4
  57.1%
1
  16.7%
0
   0.0%
2
  40.0%
3
  42.9%
1
  16.7%
6
  75.0%
3
 100.0%
5
  55.6%
3
  50.0%
1
  12.5%
4
  80.0%
5
  71.4%
39
  47.0%
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)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 6 6 3 5 6 6 6 3 6 6 6 5 6
Measure Type: Number
Unit of Measure: Participants
0 0 2 0 2 2 1 1 0 1 0 2 2 2
2.Primary Outcome
Title Maximum Tolerated Dose (MTD)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 6 6 3 5 6 6 6 3 6 6 6 5 6
Measure Type: Number
Unit of Measure: 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
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 7 6 3 5 7 6 8 3 9 6 8 5 7
Measure Type: Number
Unit of Measure: Participants
Grade 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Grade 2 2 2 3 1 2 1 0 3 0 2 1 0 1 2
Grade 3 0 5 3 2 2 3 6 4 1 4 3 6 4 3
Grade 4 1 0 0 0 0 1 0 0 1 3 1 2 0 2
Grade 5 0 0 0 0 1 2 0 1 1 0 1 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
Hide 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.
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Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 6 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
250
(9.63%)
813
(58.4%)
939
(60.0%)
5.Secondary Outcome
Title Part A: Afatinib Cmax,ss on Day 15
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 6 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 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
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 6 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
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
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 6 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
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
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 0 4 6 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 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
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 4 4 6 6
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 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
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 5 4 6 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
Day 1
3760
(53.0%)
3330
(20.8%)
5090
(38.6%)
3810
(32.9%)
3540
(40.3%)
Day 15
NA [1] 
(NA%)
NA [1] 
(NA%)
4060
(31.8%)
5290
(45.6%)
NA [1] 
(NA%)
[1]
No descriptive statistics calculated as there were no analyzable subjects.
11.Secondary Outcome
Title Part B: Paclitaxel Cmax on Day 1 and Day 15
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 6 5 6 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
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
Hide 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.
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Hide 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
Hide 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.
Overall Number of Participants Analyzed 14 14
Median (Inter-Quartile Range)
Unit of Measure: μg/mL
119
(84.2 to 159)
154
(111 to 168)
13.Secondary Outcome
Title Part C: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State in Cycle 2
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 2 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
511
(1.87%)
465
(91.8%)
14.Secondary Outcome
Title Part C: Afatinib Cmax,ss in Cycle 2
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 2 2
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 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
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 9
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 9
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
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.
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 6 2 2 2
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
326
(60.4%)
454
(61.7%)
506
(14.9%)
119
(0.110%)
18.Secondary Outcome
Title Part D: Afatinib Cmax,ss
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 7 2 2 2
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 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
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 8 7 5 6
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 8 7 5 6
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
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
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 8 7 5 7
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
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
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 8 7 5 7
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
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)
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 7 6 3 5 7 6 8 3 9 6 8 5 7
Measure Type: Number
Unit of Measure: Participants
Objective response: No 3 3 5 3 4 5 5 7 2 7 4 6 2 6
Objective response: Yes 0 4 1 0 1 2 1 1 1 2 2 2 3 1
24.Secondary Outcome
Title Objective Tumour Response (Confirmed)
Hide 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.
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 3 7 6 3 5 7 6 8 3 9 6 8 5 7
Measure Type: Number
Unit of Measure: Participants
Objective response: No 3 3 5 3 5 5 5 8 2 7 4 7 3 7
Objective response: Yes 0 4 1 0 0 2 1 0 1 2 2 1 2 0
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 [Not Specified]
 
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)
Hide 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
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/3 (66.67%)   5/7 (71.43%)   3/6 (50.00%)   1/3 (33.33%)   4/5 (80.00%)   5/7 (71.43%)   6/6 (100.00%)   5/8 (62.50%)   3/3 (100.00%)   3/9 (33.33%)   3/6 (50.00%)   5/8 (62.50%)   4/5 (80.00%)   4/7 (57.14%) 
Blood and lymphatic system disorders                             
Anaemia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Febrile neutropenia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Neutropenia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Thrombocytopenia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Cardiac disorders                             
Arrhythmia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Pericardial effusion  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Tachycardia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Gastrointestinal disorders                             
Abdominal pain  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Diarrhoea  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  1/7 (14.29%)  2/6 (33.33%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  1/7 (14.29%) 
Diarrhoea haemorrhagic  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Dysphagia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Intestinal obstruction  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Melaena  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Nausea  1  0/3 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  0/3 (0.00%)  1/5 (20.00%)  1/7 (14.29%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Small intestinal haemorrhage  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Vomiting  1  0/3 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
General disorders                             
Disease progression  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  2/3 (66.67%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Fatigue  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Mucosal inflammation  1  0/3 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Pyrexia  1  0/3 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Hepatobiliary disorders                             
Bile duct obstruction  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Immune system disorders                             
Hypersensitivity  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Infections and infestations                             
Catheter site infection  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Clostridium difficile infection  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Device related infection  1  0/3 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Device related sepsis  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Diverticulitis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Escherichia infection  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Escherichia sepsis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
H1N1 influenza  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Lobar pneumonia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Lower respiratory tract infection  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Lymphangitis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Mycobacterial infection  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Neutropenic sepsis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Paronychia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Pneumonia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Pneumonia streptococcal  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Respiratory tract infection bacterial  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Sepsis  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Staphylococcal infection  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Urinary tract infection  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Injury, poisoning and procedural complications                             
Vascular pseudoaneurysm  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Investigations                             
Blood bilirubin increased  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Metabolism and nutrition disorders                             
Dehydration  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Musculoskeletal and connective tissue disorders                             
Back pain  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Musculoskeletal pain  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                             
Cervix cancer metastatic  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Metastases to central nervous system  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Neoplasm progression  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Non-small cell lung cancer  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Non-small cell lung cancer metastatic  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Oesophageal cancer metastatic  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Pericardial effusion malignant  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Tumour haemorrhage  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Nervous system disorders                             
Dizziness  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Dystonia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Facial paresis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Headache  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Lethargy  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Neurological decompensation  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Partial seizures  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Presyncope  1  1/3 (33.33%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Seizure  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Spinal cord compression  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Syncope  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Transient ischaemic attack  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Renal and urinary disorders                             
Hydronephrosis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Renal impairment  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Urinary retention  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Reproductive system and breast disorders                             
Pelvic pain  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Respiratory, thoracic and mediastinal disorders                             
Dyspnoea  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Pleural effusion  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Pneumothorax  1  1/3 (33.33%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Pneumothorax spontaneous  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Pulmonary embolism  1  1/3 (33.33%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  1/9 (11.11%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Vascular disorders                             
Axillary vein thrombosis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Deep vein thrombosis  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  1/9 (11.11%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Hypotension  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/3 (100.00%)   7/7 (100.00%)   6/6 (100.00%)   3/3 (100.00%)   5/5 (100.00%)   7/7 (100.00%)   6/6 (100.00%)   8/8 (100.00%)   3/3 (100.00%)   9/9 (100.00%)   6/6 (100.00%)   8/8 (100.00%)   5/5 (100.00%)   7/7 (100.00%) 
Blood and lymphatic system disorders                             
Anaemia  1  1/3 (33.33%)  0/7 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  1/5 (20.00%)  1/7 (14.29%)  2/6 (33.33%)  2/8 (25.00%)  1/3 (33.33%)  2/9 (22.22%)  4/6 (66.67%)  2/8 (25.00%)  1/5 (20.00%)  3/7 (42.86%) 
Leukopenia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  3/6 (50.00%)  3/8 (37.50%)  1/5 (20.00%)  2/7 (28.57%) 
Lymph node pain  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Microcytic anaemia  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Neutropenia  1  0/3 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  2/6 (33.33%)  2/8 (25.00%)  0/3 (0.00%)  4/9 (44.44%)  5/6 (83.33%)  5/8 (62.50%)  1/5 (20.00%)  3/7 (42.86%) 
Thrombocytopenia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  3/9 (33.33%)  2/6 (33.33%)  3/8 (37.50%)  1/5 (20.00%)  2/7 (28.57%) 
Cardiac disorders                             
Bradycardia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Left ventricular dysfunction  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Palpitations  1  0/3 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Sinus tachycardia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Tachycardia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Ventricular extrasystoles  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Ear and labyrinth disorders                             
Ear discomfort  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Ear haemorrhage  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Ear pain  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Tinnitus  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Vertigo  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Eye disorders                             
Episcleritis  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Eye discharge  1  0/3 (0.00%)  0/7 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Eye pruritus  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Glaucoma  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Lacrimation increased  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Vision blurred  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Visual impairment  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Gastrointestinal disorders                             
Abdominal discomfort  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Abdominal distension  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Abdominal pain  1  0/3 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  1/3 (33.33%)  1/5 (20.00%)  2/7 (28.57%)  2/6 (33.33%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  2/8 (25.00%)  1/5 (20.00%)  4/7 (57.14%) 
Abdominal pain upper  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Cheilitis  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  1/7 (14.29%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Constipation  1  1/3 (33.33%)  2/7 (28.57%)  2/6 (33.33%)  3/3 (100.00%)  0/5 (0.00%)  3/7 (42.86%)  4/6 (66.67%)  3/8 (37.50%)  1/3 (33.33%)  2/9 (22.22%)  3/6 (50.00%)  4/8 (50.00%)  3/5 (60.00%)  2/7 (28.57%) 
Diarrhoea  1  2/3 (66.67%)  7/7 (100.00%)  6/6 (100.00%)  3/3 (100.00%)  4/5 (80.00%)  6/7 (85.71%)  4/6 (66.67%)  7/8 (87.50%)  1/3 (33.33%)  6/9 (66.67%)  6/6 (100.00%)  6/8 (75.00%)  5/5 (100.00%)  5/7 (71.43%) 
Dry mouth  1  0/3 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  2/7 (28.57%) 
Dyspepsia  1  1/3 (33.33%)  3/7 (42.86%)  2/6 (33.33%)  1/3 (33.33%)  2/5 (40.00%)  2/7 (28.57%)  1/6 (16.67%)  3/8 (37.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  2/8 (25.00%)  0/5 (0.00%)  2/7 (28.57%) 
Dysphagia  1  0/3 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Epigastric discomfort  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Flatulence  1  1/3 (33.33%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Gastric ulcer  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Gastritis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Gastrointestinal motility disorder  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Gastrooesophageal reflux disease  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  2/6 (33.33%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  3/8 (37.50%)  0/5 (0.00%)  0/7 (0.00%) 
Gingival pain  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Glossodynia  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Haemorrhoidal haemorrhage  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Haemorrhoids  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/5 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Lip dry  1  1/3 (33.33%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  1/7 (14.29%) 
Lip pain  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Melaena  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  1/7 (14.29%) 
Mouth ulceration  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Nausea  1  1/3 (33.33%)  3/7 (42.86%)  2/6 (33.33%)  1/3 (33.33%)  5/5 (100.00%)  2/7 (28.57%)  4/6 (66.67%)  5/8 (62.50%)  1/3 (33.33%)  6/9 (66.67%)  2/6 (33.33%)  3/8 (37.50%)  3/5 (60.00%)  3/7 (42.86%) 
Odynophagia  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Proctalgia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Rectal haemorrhage  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Stomatitis  1  0/3 (0.00%)  3/7 (42.86%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  2/9 (22.22%)  3/6 (50.00%)  1/8 (12.50%)  3/5 (60.00%)  0/7 (0.00%) 
Tongue discolouration  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Tongue ulceration  1  0/3 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Tooth disorder  1  1/3 (33.33%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Toothache  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Vomiting  1  1/3 (33.33%)  2/7 (28.57%)  2/6 (33.33%)  1/3 (33.33%)  2/5 (40.00%)  1/7 (14.29%)  2/6 (33.33%)  3/8 (37.50%)  0/3 (0.00%)  4/9 (44.44%)  2/6 (33.33%)  4/8 (50.00%)  1/5 (20.00%)  2/7 (28.57%) 
General disorders                             
Adverse drug reaction  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Catheter site erythema  1  0/3 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Catheter site inflammation  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Catheter site pain  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Catheter site related reaction  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Catheter site swelling  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Chest discomfort  1  1/3 (33.33%)  0/7 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  2/8 (25.00%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Chest pain  1  1/3 (33.33%)  1/7 (14.29%)  1/6 (16.67%)  0/3 (0.00%)  1/5 (20.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  3/9 (33.33%)  1/6 (16.67%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Chills  1  0/3 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  2/6 (33.33%)  1/8 (12.50%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Disease progression  1  0/3 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Early satiety  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Fatigue  1  3/3 (100.00%)  5/7 (71.43%)  5/6 (83.33%)  3/3 (100.00%)  5/5 (100.00%)  6/7 (85.71%)  4/6 (66.67%)  6/8 (75.00%)  3/3 (100.00%)  7/9 (77.78%)  5/6 (83.33%)  5/8 (62.50%)  5/5 (100.00%)  6/7 (85.71%) 
Gait disturbance  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
General physical health deterioration  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Influenza like illness  1  0/3 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Infusion site reaction  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Mucosal inflammation  1  1/3 (33.33%)  5/7 (71.43%)  4/6 (66.67%)  2/3 (66.67%)  2/5 (40.00%)  5/7 (71.43%)  2/6 (33.33%)  5/8 (62.50%)  0/3 (0.00%)  2/9 (22.22%)  2/6 (33.33%)  5/8 (62.50%)  3/5 (60.00%)  3/7 (42.86%) 
Oedema  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Oedema peripheral  1  1/3 (33.33%)  3/7 (42.86%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  1/7 (14.29%)  2/6 (33.33%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Pain  1  1/3 (33.33%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Peripheral swelling  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Pyrexia  1  3/3 (100.00%)  4/7 (57.14%)  1/6 (16.67%)  1/3 (33.33%)  2/5 (40.00%)  0/7 (0.00%)  2/6 (33.33%)  1/8 (12.50%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Suprapubic pain  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Tenderness  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Thrombosis in device  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Ulcer  1  0/3 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Hepatobiliary disorders                             
Hepatic failure  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Hyperbilirubinaemia  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Immune system disorders                             
Drug hypersensitivity  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  1/7 (14.29%) 
Infections and infestations                             
Bacteriuria  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Blister infected  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/8 (12.50%)  0/5 (0.00%)  0/7 (0.00%) 
Candida infection  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  2/7 (28.57%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  2/8 (25.00%)  0/5 (0.00%)  0/7 (0.00%) 
Catheter site cellulitis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Cellulitis  1  0/3 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Conjunctivitis  1  0/3 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  1/8 (12.50%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Cystitis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Device related infection  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/8 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Diverticulitis  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Folliculitis  1  0/3 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Fungal skin infection  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  1/5 (20.00%)  0/7 (0.00%) 
Genital abscess  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/5 (20.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Genital herpes  1  0/3 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/5 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/8 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  0/8 (0.00%)  0/5 (0.00%)  0/7 (0.00%) 
Gingivitis&nb