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

Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT00998296
Collaborator
(none)
70
Enrollment
1
Location
1
Arm
57
Duration (Months)
1.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
  • Drug: BIBW 2992
  • Drug: BIBF 1120
 Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
70 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I Dose Escalation Study of Concomitant BIBF 1120 and BIBW 2992 in Patients With Advanced Solid Tumours.
Study Start Date :
Oct 1, 2009
Actual Primary Completion Date :
Dec 1, 2012
Actual Study Completion Date :
Jul 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: BIBW 2992 + BIBF 1120

This is a phase I dose escalation clinical trial and the data obtained shall determine the MTD for the combination of BIBW 2992/BIBF 1120 in 28-day of treatment.

Drug: BIBW 2992
EGFR inhibitor

Drug: BIBF 1120
VEGF inhibitor

Outcome Measures

Primary Outcome Measures

  1. Maximum Tolerated Dose (MTD) of Nintedanib and Afatinib Based on the Percentage of Participants Experienced Dose Limiting Toxicities [first treatment cycle, up to 28 days]

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

Secondary Outcome Measures

  1. Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1 [6 weeks]

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

  2. Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0 [First treatment administration until cut-off date of 02Oct2014; up to 336 days]

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

  3. Changes in Safety Laboratory Parameters [First treatment administration until cut-off date of 02 October 2014, up to 336 days]

    Changes in safety laboratory Parameters reported as adverse events

  4. Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State) [Day 8, Day 15, Day 22 and Day 28]

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

  5. Trough Plasma Concentration of Afatinib at Steady State [Day 7, Day 13, Day 15, Day 22, Day 27 and Day 28]

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

  6. Objective Response (OR) During the Expansion Phase [Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)]

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

  7. Disease Control (DC) During the Expansion Phase [Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)]

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

  8. Stable Disease for at Least 12 Weeks During the Expansion Phase [Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)]

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

  9. Percentage Change in the Tumour Size From Baseline During the Expansion Phase [Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)]

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

Eligibility Criteria

Criteria

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

  1. Patients with confirmed histological or cytological diagnosis of advanced solid tumours and for whom no proven therapy exists or who are not amenable to established treatments.

  2. Age 18 years or older.

  3. Life expectancy of at least three months.

  4. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.

  5. Patients previously treated and with asymptomatic brain metastases are eligible

  6. Patients must have recovered from recent surgery.

Exclusion criteria:

  1. Active infectious disease

  2. Recent surgery within the last 4 weeks prior visit 1.

  3. Chronic diarrhoea or gastrointestinal tract disease resulting in an inability to take oral medication

  4. History of haemorrhagic or thrombotic events

  5. Significant cardiovascular diseases within

  6. Current peripheral neuropathy > Common Terminology Criteria for Adverse Events (CTCAE) grade 1 except due to trauma

  7. Untreated or symptomatic brain metastases or leptomeningeal disease.

  8. Treatment with an Epidermal growth Factor-receptor (EGFR)- or Heregulin Receptor 2 (HER2) inhibiting drug or antiangiogenic drug.

  9. Therapeutic anticoagulation.

  10. Female patients of childbearing potential.

  11. Known pre-existing interstitial lung disease

Contacts and Locations

Locations

Site City State Country Postal Code
1 1239.14.3301A Boehringer Ingelheim Investigational Site Villejuif Cedex France

Sponsors and Collaborators

  • Boehringer Ingelheim

Investigators

  • Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00998296
Other Study ID Numbers:
  • 1239.14
  • 2009-011321-14
First Posted:
Oct 20, 2009
Last Update Posted:
Aug 19, 2015
Last Verified:
Jul 1, 2015
Additional relevant MeSH terms:
Nintedanib
Afatinib

Study Results

Participant Flow

Recruitment Details Trial consisted of a dose-escalation phase (to determine the maximum tolerated dose (MTD) of treatments administered concomitantly) and an expansion phase(to assess the safety and the preliminary anti-tumour activity of the combination therapy at the previously determined MTD in patients with non-small cell lung cancer or pancreatic adenocarcinoma)
Pre-assignment Detail
Arm/Group Title Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuously Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently NSCLC Pancreatic Adenocarcinoma
Arm/Group Description Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 10 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 20 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the "expansion phase" which follows on the dose-escalation phase.
Period Title: Overall Study
STARTED 6 3 3 3 8 3 7 6 6 18 7
COMPLETED 6 2 3 3 6 3 6 4 4 0 0
NOT COMPLETED 0 1 0 0 2 0 1 2 2 18 7

Baseline Characteristics

Arm/Group Title Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuously Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently NSCLC Pancreatic Adenocarcinoma Total
Arm/Group Description Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 10 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 20 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the "expansion phase" which follows on the dose-escalation phase. Total of all reporting groups
Overall Participants 6 3 3 3 8 3 7 6 6 18 7 70
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
53.7
(8.1)
51.7
(1.5)
46.7
(4.9)
53.3
(11.0)
51.5
(9.7)
44.3
(8.1)
64.9
(3.5)
52.2
(6.0)
63.3
(10.3)
58.1
(10.9)
58.1
(6.8)
56.0
(9.7)
Sex: Female, Male (Count of Participants)
Female
3
50%
1
33.3%
0
0%
1
33.3%
6
75%
2
66.7%
0
0%
4
66.7%
2
33.3%
11
61.1%
1
14.3%
31
44.3%
Male
3
50%
2
66.7%
3
100%
2
66.7%
2
25%
1
33.3%
7
100%
2
33.3%
4
66.7%
7
38.9%
6
85.7%
39
55.7%

Outcome Measures

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

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuously Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently
Arm/Group Description Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 10 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 20 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase".
Measure Participants 6 3 3 3 8 3 7 6 6
Alanine aminotransferase increased
0.0
0%
0.0
0%
0.0
0%
0.0
0%
12.5
156.3%
33.3
1110%
0.0
0%
0.0
0%
0.0
0%
Aspartate aminotransferase increased
0.0
0%
0.0
0%
0.0
0%
0.0
0%
12.5
156.3%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
Blood creatinine increased
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
33.3
1110%
0.0
0%
16.7
278.3%
0.0
0%
Dehydration
0.0
0%
33.3
1110%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
16.7
278.3%
Diarrhoea
0.0
0%
33.3
1110%
0.0
0%
0.0
0%
25.0
312.5%
33.3
1110%
0.0
0%
16.7
278.3%
0.0
0%
Hepatocellular injury
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
33.3
1110%
0.0
0%
16.7
278.3%
0.0
0%
Renal failure acute
0.0
0%
66.7
2223.3%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
Hepatotoxicity
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
16.7
278.3%
2. Secondary Outcome
Title Overall Tumour Response Rate Assessed by the Investigator According to the Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1
Description The investigator evaluated whether complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) occurred in a patient. CR for target lesions: Disappearance of all target lesions. CR for non-target lesions: Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (<10mm short axis). PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study. PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions
Time Frame 6 weeks

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuously Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently NSCLC Pancreatic Adenocarcinoma
Arm/Group Description Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 10 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 20 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the "expansion phase" which follows on the dose-escalation phase.
Measure Participants 6 3 3 3 7 3 6 6 3 17 6
Complete response
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
Partial response
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
0.0
0%
17.6
97.8%
0.0
0%
Stable disease
66.7
1111.7%
66.7
2223.3%
66.7
2223.3%
33.3
1110%
71.4
892.5%
100
3333.3%
66.7
952.9%
83.3
1388.3%
100.0
1666.7%
70.6
392.2%
33.3
475.7%
Progressive disease
33.3
555%
33.3
1110%
33.3
1110%
66.7
2223.3%
28.6
357.5%
0.0
0%
33.3
475.7%
16.7
278.3%
0.0
0%
11.8
65.6%
66.6
951.4%
3. Secondary Outcome
Title Incidence and Intensity of Adverse Events According to CTCAE (Common Toxicity Criteria Adverse Event) Version 3.0
Description Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).
Time Frame First treatment administration until cut-off date of 02Oct2014; up to 336 days

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuously Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently NSCLC Pancreatic Adenocarcinoma
Arm/Group Description Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 10 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 20 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the "expansion phase" which follows on the dose-escalation phase.
Measure Participants 6 3 3 3 8 3 7 6 6 18 7
CTCAE Grade 1
1
16.7%
0
0%
0
0%
0
0%
0
0%
0
0%
1
14.3%
0
0%
0
0%
0
0%
1
14.3%
CTCAE Grade 2
2
33.3%
0
0%
1
33.3%
2
66.7%
1
12.5%
0
0%
2
28.6%
4
66.7%
0
0%
7
38.9%
2
28.6%
CTCAE Grade 3
1
16.7%
2
66.7%
2
66.7%
1
33.3%
5
62.5%
2
66.7%
4
57.1%
2
33.3%
3
50%
7
38.9%
2
28.6%
CTCAE Grade 4
2
33.3%
0
0%
0
0%
0
0%
1
12.5%
1
33.3%
0
0%
0
0%
2
33.3%
2
11.1%
2
28.6%
CTCAE Grade 5
0
0%
1
33.3%
0
0%
0
0%
1
12.5%
0
0%
0
0%
0
0%
1
16.7%
2
11.1%
0
0%
4. Secondary Outcome
Title Changes in Safety Laboratory Parameters
Description Changes in safety laboratory Parameters reported as adverse events
Time Frame First treatment administration until cut-off date of 02 October 2014, up to 336 days

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuously Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently NSCLC Pancreatic Adenocarcinoma
Arm/Group Description Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 10 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 20 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase". Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the "expansion phase" which follows on the dose-escalation phase.
Measure Participants 6 3 3 3 8 3 7 6 6 18 7
Alanine aminotransferase increased
1
16.7%
1
33.3%
1
33.3%
1
33.3%
3
37.5%
3
100%
1
14.3%
3
50%
3
50%
1
5.6%
1
14.3%
Aspartate aminotransferase increased
1
16.7%
1
33.3%
1
33.3%
0
0%
3
37.5%
3
100%
1
14.3%
2
33.3%
1
16.7%
1
5.6%
2
28.6%
Blood creatinine increased
1
16.7%
0
0%
0
0%
0
0%
1
12.5%
1
33.3%
1
14.3%
1
16.7%
1
16.7%
1
5.6%
0
0%
Blood alkaline phosphatase increased
0
0%
1
33.3%
1
33.3%
0
0%
1
12.5%
0
0%
0
0%
1
16.7%
0
0%
0
0%
0
0%
Blood bilirubin increased
0
0%
0
0%
1
33.3%
0
0%
0
0%
1
33.3%
0
0%
0
0%
0
0%
0
0%
2
28.6%
Troponin increased
0
0%
1
33.3%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Gamma-glutamyltransferase increased
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
4
57.1%
1
16.7%
0
0%
0
0%
0
0%
Blood creatinine phosphokinase increased
0
0%
0
0%
0
0%
1
33.3%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Blood fibrinogen increased
0
0%
0
0%
0
0%
1
33.3%
0
0%
0
0%
1
14.3%
0
0%
0
0%
0
0%
0
0%
Hepatic enzymes increased
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
16.7%
0
0%
0
0%
5. Secondary Outcome
Title Cpre,ss,Norm (Dose Normalized Trough Plasma Concentration of Nintedanib at Steady State)
Description Cpre,ss,norm (Dose normalized trough plasma concentration of nintedanib at steady state) are presented for the 2 MTD treatment groups (continuous administered nintedanib at 150 mg b.i.d. concomitantly with continuously administered afatinib 30 mg q.d. or with intermittently administered afatinib 40 mg q.d.) As nintedanib is given twice daily, samples are taken at Day 8, Day 15, Day 22 and Day 28; the Pharmacokinetic (PK) parameter names will be Cpre,ss,15,norm (Day 8), Cpre,ss,29,norm (Day 15), Cpre,ss,43,norm (Day 22) and Cpre,ss,55,norm (Day 28)
Time Frame Day 8, Day 15, Day 22 and Day 28

Outcome Measure Data

Analysis Population Description
PKS. Only 6 patients were planned to be treated in the "Nintedanib 150 mg +Afatinib 30 mg- Continuously" group. Nevertheless, the patients were allowed to reduce their dose and by the way they changed the group and came in the "Nintedanib 150 mg +Afatinib 30 mg- Continuously" group with at the end N = 8 evaluable concentrations instead of 6 planned
Arm/Group Title Nintedanib 150 mg +Afatinib 30 mg- Continuously Nintedanib 150 mg +Afatinib 40 mg- Intermittently
Arm/Group Description Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase".
Measure Participants 8 7
Cpre,ss,15,norm (N= 6, 7)
0.122
(155)
0.0731
(92.2)
Cpre,ss,29,norm (N= 6, 6)
0.0948
(136)
0.0755
(148)
Cpre,ss,43,norm (N= 5, 6)
0.112
(125)
0.0762
(79.7)
Cpre,ss,55,norm (N= 8, NA)
0.0797
(247)
NA
(NA)
6. Secondary Outcome
Title Trough Plasma Concentration of Afatinib at Steady State
Description C(pre,ss) is defined as pre-dose (trough) concentration of afatinib in plasma at steady state immediately before administration of the next dose. C24,7 corresponds to the plasma concentration at 24 hours on Day 7. C24,13 corresponds to the plasma concentration at 24 hours on Day 13. C24,27 corresponds to the plasma concentration at 24 hours on Day 27.
Time Frame Day 7, Day 13, Day 15, Day 22, Day 27 and Day 28

Outcome Measure Data

Analysis Population Description
PKS. Only 6 patients were planned to be treated in the "Nintedanib 150 mg +Afatinib 30 mg- Continuously" group. Nevertheless, the patients were allowed to reduce their dose and by the way they changed the group and came in the "Nintedanib 150 mg +Afatinib 30 mg- Continuously" group with at the end N = 8 evaluable concentrations instead of 6 planned
Arm/Group Title Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently
Arm/Group Description Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 30 mg was given continuously once daily (q.d.). This is a part of the "dose-escalation phase". Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, film-coated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week. This is a part of the "dose-escalation phase".
Measure Participants 8 7
Cpre,ss,15 (N= 6, NA)
15.5
(62.0)
NA
(NA)
Cpre,ss,22 (N= 6, NA)
19.0
(56.5)
NA
(NA)
Cpre,ss,28 (N= 8, NA)
19.1
(63.3)
NA
(NA)
C24,7 (N= NA, 6)
NA
(NA)
19.6
(127.0)
C24,13 (N= NA, 5)
NA
(NA)
11.5
(76.4)
C24,27 (N= NA, 2)
NA
(NA)
30.5
(21.9)
7. Secondary Outcome
Title Objective Response (OR) During the Expansion Phase
Description OR is defined as a best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.1, CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions. All lymph nodes must be nonpathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below: CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; All the above scenarios should also satisfy 'No occurrence of new lesions'.
Time Frame Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title NSCLC Pancreatic Adenocarcinoma
Arm/Group Description Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the "expansion phase" which follows on the dose-escalation phase.
Measure Participants 18 7
Yes
22.2
370%
0.0
0%
No
72.2
1203.3%
85.7
2856.7%
Missing
5.6
93.3%
14.3
476.7%
8. Secondary Outcome
Title Disease Control (DC) During the Expansion Phase
Description DC is defined as the best overall response of CR, PR, stable disease (SD) and non-CR/non-PD. CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions . All lymph nodes must be non-pathological in size (<10mm short axis). PR for TL: At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- CR in TL, but non-CR/Non-PD in NTL leads to PR CR in TL, but not evaluated NTL leads to PR PR in TL, but non-PD NTL or not all evaluated NTL leads to PR; SD for TL: change in the sum of diameters does not satisfy PR or PD. SD in TL, non-PD in NTL lead to overall response of SD, provided there is no appearance of new lesions.
Time Frame Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title NSCLC Pancreatic Adenocarcinoma
Arm/Group Description Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the "expansion phase" which follows on the dose-escalation phase.
Measure Participants 18 7
Yes
83.3
1388.3%
28.6
953.3%
No
11.1
185%
57.1
1903.3%
Missing
5.6
93.3%
14.3
476.7%
9. Secondary Outcome
Title Stable Disease for at Least 12 Weeks During the Expansion Phase
Description SD: Neither sufficient shrinkage to qualify for PR (Partial response) nor sufficient increase to qualify for PD(Progressive disease), taking as references the smallest sum of diameters SoD while on study. PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions.
Time Frame Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title NSCLC Pancreatic Adenocarcinoma
Arm/Group Description Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the "expansion phase" which follows on the dose-escalation phase.
Measure Participants 18 7
Yes
44.4
740%
0.0
0%
No
50.0
833.3%
85.7
2856.7%
Missing
5.6
93.3%
14.3
476.7%
10. Secondary Outcome
Title Percentage Change in the Tumour Size From Baseline During the Expansion Phase
Description Percentage change in the tumour size from baseline is expressed as Number of subjects with maximum decrease from baseline in the sum of longest diameters of target lesions.
Time Frame Tumour assessment was to be performed at Screening, every 6 weeks after starting study treatment until disease progression, and at the end-of-treatment (EOT) visit (up to 1117 days)

Outcome Measure Data

Analysis Population Description
Treated set
Arm/Group Title NSCLC Pancreatic Adenocarcinoma
Arm/Group Description Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg bid plus film-coated tablet of Afatinib 30 mg qd). This is a part of the "expansion phase" which follows on the dose-escalation phase.
Measure Participants 16 6
>=20%
1
16.7%
3
100%
>=0% and <20%
4
66.7%
3
100%
>-30% and <0%
6
100%
0
0%
<-30%
5
83.3%
0
0%

Adverse Events

Time Frame First treatment administration until cut-off date of 02Oct2014; up to 336 days
Adverse Event Reporting Description
Arm/Group Title Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuosly Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently NSCLC Pancreatic Adenocarcinoma
Arm/Group Description Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, filmcoated tablet of Afatinib 30 mg was given continuously once daily (q.d.) Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, filmcoated tablet of Afatinib 40 mg was given continuously once daily (q.d.) Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, filmcoated tablet of Afatinib 10 mg was given continuously once daily (q.d.) Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, filmcoated tablet of Afatinib 20 mg was given continuously once daily (q.d.) Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, filmcoated tablet of Afatinib 30 mg was given continuously once daily (q.d.) Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, filmcoated tablet of Afatinib 40 mg was given continuously once daily (q.d.) Patients receiving oral administration of soft-gelatine capsule of Nintedanib 150 mg continuously twice daily (b.i.d.); concomitantly, filmcoated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, filmcoated tablet of Afatinib 30 mg was given intermittently once daily (q.d.) every other week Patients receiving oral administration of soft-gelatine capsule of Nintedanib 200 mg continuously twice daily (b.i.d.); concomitantly, filmcoated tablet of Afatinib 40 mg was given intermittently once daily (q.d.) every other week Patients with non-small cell lung cancer (NSCLC) receiving the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d.) plus film-coated tablet of Afatinib 30 mg (q.d.)). This is a part of the "expansion phase" which follows on the dose-escalation phase. Patients with Pancreatic adenocarcinoma were to be treated with the study drug combination at the maximum tolerated dose (MTD) level determined for continuous afatinib and nintedanib dosing during the dose-escalation phase (oral administration of soft-gelatine capsule of Nintedanib 150 mg (b.i.d) plus film-coated tablet of Afatinib 30 mg (q.d)). This is a part of the "expansion phase" which follows on the dose-escalation phase.
All Cause Mortality
Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuosly Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently NSCLC Pancreatic Adenocarcinoma
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
Serious Adverse Events
Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuosly Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently NSCLC Pancreatic Adenocarcinoma
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 3/6 (50%) 3/3 (100%) 1/3 (33.3%) 0/3 (0%) 7/8 (87.5%) 3/3 (100%) 1/7 (14.3%) 1/6 (16.7%) 4/6 (66.7%) 7/18 (38.9%) 3/7 (42.9%)
Blood and lymphatic system disorders
Anaemia 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Thrombotic microangiopathy 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Gastrointestinal disorders
Abdominal pain upper 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Diarrhoea 2/6 (33.3%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/8 (37.5%) 1/3 (33.3%) 1/7 (14.3%) 1/6 (16.7%) 0/6 (0%) 2/18 (11.1%) 1/7 (14.3%)
Pancreatitis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Vomiting 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
General disorders
Asthenia 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
General physical health deterioration 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hyperthermia 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Oedema peripheral 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Pain 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 1/7 (14.3%)
Pyrexia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Hepatobiliary disorders
Bile duct obstruction 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Cholangitis 0/6 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Cholecystitis 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hepatocellular injury 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hepatotoxicity 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Infections and infestations
Catheter site infection 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Lung infection 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Pneumonia pneumococcal 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Investigations
Alanine aminotransferase increased 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Aspartate aminotransferase increased 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Blood creatinine increased 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 1/7 (14.3%)
Metabolism and nutrition disorders
Decreased appetite 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 1/7 (14.3%)
Dehydration 2/6 (33.3%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 2/18 (11.1%) 0/7 (0%)
Hypokalaemia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Metastases to ovary 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Nervous system disorders
Ischaemic stroke 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Renal and urinary disorders
Renal failure 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 1/7 (14.3%)
Renal failure acute 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 2/6 (33.3%) 0/18 (0%) 0/7 (0%)
Urinary retention 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Haemoptysis 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Obstructive airways disorder 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 1/7 (14.3%)
Pleural effusion 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Pulmonary embolism 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Respiratory failure 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Skin and subcutaneous tissue disorders
Subcutaneous nodule 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 1/7 (14.3%)
Surgical and medical procedures
Oesophageal operation 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Other (Not Including Serious) Adverse Events
Nintedanib 150 mg +Afatinib 30 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Continuously Nintedanib 200 mg +Afatinib 10 mg - Continuously Nintedanib 200 mg +Afatinib 20 mg - Continuosly Nintedanib 200 mg +Afatinib 30 mg - Continuously Nintedanib 200 mg +Afatinib 40 mg - Continuously Nintedanib 150 mg +Afatinib 40 mg - Intermittently Nintedanib 200 mg +Afatinib 30 mg - Intermittently Nintedanib 200 mg +Afatinib 40 mg - Intermittently NSCLC Pancreatic Adenocarcinoma
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 6/6 (100%) 3/3 (100%) 3/3 (100%) 3/3 (100%) 8/8 (100%) 3/3 (100%) 7/7 (100%) 6/6 (100%) 6/6 (100%) 18/18 (100%) 6/7 (85.7%)
Blood and lymphatic system disorders
Anaemia 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Eosinophilia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Thrombocytopenia 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Thrombocytosis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 2/6 (33.3%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Congenital, familial and genetic disorders
Pyloric stenosis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Ear and labyrinth disorders
Ear pain 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Tinnitus 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Vertigo 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Eye disorders
Blepharitis 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Conjunctivitis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Dry eye 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 2/6 (33.3%) 1/18 (5.6%) 0/7 (0%)
Lacrimation increased 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Visual acuity reduced 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Visual impairment 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 1/18 (5.6%) 0/7 (0%)
Gastrointestinal disorders
Abdominal distension 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Abdominal pain 0/6 (0%) 1/3 (33.3%) 2/3 (66.7%) 1/3 (33.3%) 4/8 (50%) 0/3 (0%) 0/7 (0%) 2/6 (33.3%) 1/6 (16.7%) 4/18 (22.2%) 2/7 (28.6%)
Abdominal pain lower 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Abdominal pain upper 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 2/3 (66.7%) 0/8 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Aerophagia 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Aphthous stomatitis 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 3/3 (100%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Ascites 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Cheilitis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 2/7 (28.6%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Constipation 1/6 (16.7%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 2/8 (25%) 0/3 (0%) 2/7 (28.6%) 0/6 (0%) 2/6 (33.3%) 2/18 (11.1%) 0/7 (0%)
Diarrhoea 6/6 (100%) 3/3 (100%) 3/3 (100%) 3/3 (100%) 8/8 (100%) 3/3 (100%) 6/7 (85.7%) 6/6 (100%) 6/6 (100%) 14/18 (77.8%) 6/7 (85.7%)
Dry mouth 1/6 (16.7%) 2/3 (66.7%) 2/3 (66.7%) 2/3 (66.7%) 2/8 (25%) 2/3 (66.7%) 2/7 (28.6%) 2/6 (33.3%) 1/6 (16.7%) 3/18 (16.7%) 0/7 (0%)
Dyspepsia 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Dysphagia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Flatulence 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 4/6 (66.7%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Gastrooesophageal reflux disease 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 2/18 (11.1%) 0/7 (0%)
Gingival bleeding 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Glossodynia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Haematemesis 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Haemorrhoids 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 2/18 (11.1%) 0/7 (0%)
Melaena 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Nausea 4/6 (66.7%) 3/3 (100%) 2/3 (66.7%) 3/3 (100%) 4/8 (50%) 2/3 (66.7%) 4/7 (57.1%) 3/6 (50%) 5/6 (83.3%) 12/18 (66.7%) 3/7 (42.9%)
Odynophagia 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Oesophageal pain 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Oesophagitis haemorrhagic 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Periodontal disease 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Rectal haemorrhage 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Rectal tenesmus 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Stomatitis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 1/7 (14.3%)
Tongue coated 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Tongue dry 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Vomiting 1/6 (16.7%) 3/3 (100%) 1/3 (33.3%) 2/3 (66.7%) 5/8 (62.5%) 3/3 (100%) 3/7 (42.9%) 5/6 (83.3%) 5/6 (83.3%) 6/18 (33.3%) 0/7 (0%)
General disorders
Asthenia 6/6 (100%) 3/3 (100%) 2/3 (66.7%) 3/3 (100%) 8/8 (100%) 3/3 (100%) 5/7 (71.4%) 2/6 (33.3%) 3/6 (50%) 13/18 (72.2%) 2/7 (28.6%)
Axillary pain 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Chest pain 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Chills 0/6 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Face oedema 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Fatigue 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 1/18 (5.6%) 0/7 (0%)
Feeling hot 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Inflammation 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Mucosal dryness 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Mucosal inflammation 2/6 (33.3%) 2/3 (66.7%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 2/3 (66.7%) 0/7 (0%) 1/6 (16.7%) 3/6 (50%) 5/18 (27.8%) 0/7 (0%)
Oedema 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 2/18 (11.1%) 0/7 (0%)
Oedema peripheral 1/6 (16.7%) 1/3 (33.3%) 2/3 (66.7%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 1/7 (14.3%)
Pain 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Pyrexia 2/6 (33.3%) 2/3 (66.7%) 2/3 (66.7%) 1/3 (33.3%) 2/8 (25%) 0/3 (0%) 0/7 (0%) 2/6 (33.3%) 2/6 (33.3%) 1/18 (5.6%) 1/7 (14.3%)
Thirst 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Xerosis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 2/18 (11.1%) 0/7 (0%)
Hepatobiliary disorders
Cholestasis 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hepatocellular injury 0/6 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 1/8 (12.5%) 1/3 (33.3%) 1/7 (14.3%) 4/6 (66.7%) 2/6 (33.3%) 2/18 (11.1%) 1/7 (14.3%)
Hyperbilirubinaemia 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Immune system disorders
Iodine allergy 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Infections and infestations
Bronchitis 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Candida infection 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Cystitis 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Ear infection 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Folliculitis 4/6 (66.7%) 3/3 (100%) 0/3 (0%) 2/3 (66.7%) 4/8 (50%) 1/3 (33.3%) 4/7 (57.1%) 2/6 (33.3%) 3/6 (50%) 0/18 (0%) 0/7 (0%)
Furuncle 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Genital infection fungal 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Herpes virus infection 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Infection 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Laryngitis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Lung infection 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Lymphangitis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Nasopharyngitis 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 2/6 (33.3%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Oral candidiasis 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Oral fungal infection 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Oral herpes 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Paronychia 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Purulent discharge 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Rash pustular 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Rhinitis 3/6 (50%) 1/3 (33.3%) 3/3 (100%) 3/3 (100%) 4/8 (50%) 2/3 (66.7%) 1/7 (14.3%) 0/6 (0%) 2/6 (33.3%) 5/18 (27.8%) 1/7 (14.3%)
Skin infection 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Tracheitis 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Urinary tract infection 1/6 (16.7%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 2/8 (25%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 2/18 (11.1%) 0/7 (0%)
Injury, poisoning and procedural complications
Gastroenteritis radiation 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Gastrointestinal stoma complication 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Medication error 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Periorbital haemorrhage 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Post procedural haemorrhage 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Investigations
Alanine aminotransferase increased 1/6 (16.7%) 1/3 (33.3%) 1/3 (33.3%) 1/3 (33.3%) 2/8 (25%) 3/3 (100%) 1/7 (14.3%) 3/6 (50%) 3/6 (50%) 1/18 (5.6%) 1/7 (14.3%)
Aspartate aminotransferase increased 1/6 (16.7%) 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 2/8 (25%) 3/3 (100%) 1/7 (14.3%) 2/6 (33.3%) 1/6 (16.7%) 1/18 (5.6%) 2/7 (28.6%)
Blood alkaline phosphatase increased 0/6 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Blood bilirubin increased 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 2/7 (28.6%)
Blood creatine phosphokinase increased 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Blood creatinine increased 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 1/3 (33.3%) 0/7 (0%) 1/6 (16.7%) 1/6 (16.7%) 1/18 (5.6%) 0/7 (0%)
Blood fibrinogen increased 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Ejection fraction decreased 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Electrocardiogram repolarisation abnormality 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Gamma-glutamyltransferase increased 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 4/7 (57.1%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hepatic enzyme increased 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Troponin increased 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Weight decreased 1/6 (16.7%) 2/3 (66.7%) 0/3 (0%) 1/3 (33.3%) 2/8 (25%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 2/6 (33.3%) 4/18 (22.2%) 1/7 (14.3%)
Metabolism and nutrition disorders
Decreased appetite 3/6 (50%) 3/3 (100%) 1/3 (33.3%) 2/3 (66.7%) 3/8 (37.5%) 3/3 (100%) 4/7 (57.1%) 6/6 (100%) 4/6 (66.7%) 11/18 (61.1%) 2/7 (28.6%)
Dehydration 0/6 (0%) 2/3 (66.7%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 2/3 (66.7%) 2/7 (28.6%) 2/6 (33.3%) 3/6 (50%) 0/18 (0%) 0/7 (0%)
Hypercreatininaemia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hyperglycaemia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hyperkalaemia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 2/6 (33.3%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Hyperlipasaemia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Hyperuricaemia 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hypocalcaemia 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 2/7 (28.6%) 2/6 (33.3%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Hypokalaemia 2/6 (33.3%) 2/3 (66.7%) 0/3 (0%) 2/3 (66.7%) 2/8 (25%) 1/3 (33.3%) 2/7 (28.6%) 1/6 (16.7%) 2/6 (33.3%) 4/18 (22.2%) 0/7 (0%)
Hypomagnesaemia 1/6 (16.7%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 1/7 (14.3%) 1/6 (16.7%) 2/6 (33.3%) 5/18 (27.8%) 0/7 (0%)
Hyponatraemia 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 1/6 (16.7%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Hypoproteinaemia 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Metabolic acidosis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/6 (0%) 0/3 (0%) 2/3 (66.7%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 2/18 (11.1%) 0/7 (0%)
Back pain 1/6 (16.7%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 1/18 (5.6%) 0/7 (0%)
Bone pain 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Clubbing 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Flank pain 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Muscle spasms 2/6 (33.3%) 0/3 (0%) 2/3 (66.7%) 1/3 (33.3%) 2/8 (25%) 1/3 (33.3%) 2/7 (28.6%) 1/6 (16.7%) 1/6 (16.7%) 5/18 (27.8%) 0/7 (0%)
Musculoskeletal chest pain 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Musculoskeletal pain 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Myalgia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Pain in extremity 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Trismus 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Metastases to liver 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Tumour haemorrhage 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Nervous system disorders
Cervical root pain 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Dizziness 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Dizziness postural 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Dysgeusia 1/6 (16.7%) 1/3 (33.3%) 2/3 (66.7%) 2/3 (66.7%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Headache 1/6 (16.7%) 1/3 (33.3%) 2/3 (66.7%) 2/3 (66.7%) 0/8 (0%) 2/3 (66.7%) 0/7 (0%) 1/6 (16.7%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Hyperaesthesia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Memory impairment 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Motor dysfunction 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Neuralgia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Paraesthesia 2/6 (33.3%) 2/3 (66.7%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 2/6 (33.3%) 2/6 (33.3%) 0/18 (0%) 0/7 (0%)
Parosmia 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Sciatica 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Somnolence 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Tremor 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Psychiatric disorders
Anxiety 0/6 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 2/3 (66.7%) 1/7 (14.3%) 2/6 (33.3%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Confusional state 1/6 (16.7%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Depression 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 1/3 (33.3%) 1/7 (14.3%) 0/6 (0%) 1/6 (16.7%) 2/18 (11.1%) 0/7 (0%)
Expressive language disorder 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Insomnia 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/8 (12.5%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 1/7 (14.3%)
Irritability 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Libido disorder 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Mood altered 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/8 (12.5%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 1/18 (5.6%) 0/7 (0%)
Psychomotor retardation 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Sleep disorder 0/6 (0%) 1/3 (33.3%) 2/3 (66.7%) 1/3 (33.3%) 2/8 (25%) 1/3 (33.3%) 0/7 (0%) 1/6 (16.7%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Renal and urinary disorders
Calculus urinary 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Dysuria 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Haematuria 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Incontinence 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Pollakiuria 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 1/7 (14.3%)
Proteinuria 2/6 (33.3%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/8 (25%) 0/3 (0%) 1/7 (14.3%) 2/6 (33.3%) 0/6 (0%) 1/18 (5.6%) 1/7 (14.3%)
Renal failure 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/8 (25%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 1/6 (16.7%) 2/18 (11.1%) 0/7 (0%)
Renal failure acute 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Urinary bladder haemorrhage 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Urinary retention 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Urinary tract obstruction 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Reproductive system and breast disorders
Erectile dysfunction 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Gynaecomastia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Vulvovaginal discomfort 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Vulvovaginal pruritus 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Cough 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 3/3 (100%) 3/8 (37.5%) 0/3 (0%) 1/7 (14.3%) 1/6 (16.7%) 2/6 (33.3%) 3/18 (16.7%) 0/7 (0%)
Dysphonia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/8 (25%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 3/18 (16.7%) 3/7 (42.9%)
Dyspnoea 0/6 (0%) 2/3 (66.7%) 2/3 (66.7%) 3/3 (100%) 0/8 (0%) 1/3 (33.3%) 2/7 (28.6%) 2/6 (33.3%) 1/6 (16.7%) 4/18 (22.2%) 0/7 (0%)
Epistaxis 2/6 (33.3%) 2/3 (66.7%) 2/3 (66.7%) 3/3 (100%) 5/8 (62.5%) 2/3 (66.7%) 1/7 (14.3%) 0/6 (0%) 2/6 (33.3%) 3/18 (16.7%) 0/7 (0%)
Haemoptysis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hiccups 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Nasal dryness 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Nasal obstruction 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Oropharyngeal pain 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Productive cough 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Rhinalgia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Rhinorrhoea 2/6 (33.3%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 1/3 (33.3%) 1/7 (14.3%) 0/6 (0%) 1/6 (16.7%) 3/18 (16.7%) 1/7 (14.3%)
Skin and subcutaneous tissue disorders
Alopecia 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Dermatitis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Dermatitis acneiform 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Dermatitis allergic 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Drug eruption 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Dry skin 1/6 (16.7%) 1/3 (33.3%) 2/3 (66.7%) 2/3 (66.7%) 4/8 (50%) 1/3 (33.3%) 3/7 (42.9%) 3/6 (50%) 0/6 (0%) 5/18 (27.8%) 0/7 (0%)
Eczema 0/6 (0%) 0/3 (0%) 2/3 (66.7%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Erythema 1/6 (16.7%) 0/3 (0%) 2/3 (66.7%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Hyperkeratosis 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hypertrichosis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Macule 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Nail dystrophy 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Nail growth abnormal 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Nail ridging 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Night sweats 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 2/6 (33.3%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Onychoclasis 3/6 (50%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Pain of skin 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Palmar-plantar erythrodysaesthesia syndrome 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Papule 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Photosensitivity reaction 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Pruritus 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/8 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/6 (0%) 1/6 (16.7%) 2/18 (11.1%) 1/7 (14.3%)
Rash 2/6 (33.3%) 0/3 (0%) 2/3 (66.7%) 1/3 (33.3%) 1/8 (12.5%) 2/3 (66.7%) 1/7 (14.3%) 1/6 (16.7%) 1/6 (16.7%) 11/18 (61.1%) 4/7 (57.1%)
Rash erythematous 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Rash macular 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Rash maculo-papular 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Scab 1/6 (16.7%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Skin burning sensation 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Skin exfoliation 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/8 (37.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Skin fissures 2/6 (33.3%) 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 5/8 (62.5%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 5/18 (27.8%) 0/7 (0%)
Skin irritation 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Skin lesion 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Skin toxicity 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 1/7 (14.3%)
Skin ulcer 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Solar dermatitis 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Xeroderma 0/6 (0%) 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 0/8 (0%) 1/3 (33.3%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Vascular disorders
Haematoma 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 1/6 (16.7%) 0/18 (0%) 0/7 (0%)
Haemorrhage 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Hot flush 0/6 (0%) 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 2/18 (11.1%) 0/7 (0%)
Hypertension 0/6 (0%) 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/8 (12.5%) 0/3 (0%) 1/7 (14.3%) 0/6 (0%) 0/6 (0%) 1/18 (5.6%) 0/7 (0%)
Hypotension 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/8 (0%) 0/3 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/6 (0%) 0/18 (0%) 0/7 (0%)
Lymphoedema 0/6 (0%) 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/8 (12.5%) 0/3 (0%) 0/7 (0%) 0/6 (0%) 0/6 (0%) 0/18 (0%) 0/7 (0%)

Limitations/Caveats

Statistics of PK parameters are only estimated when at least 2/3 of the data are evaluable.

More Information

Certain Agreements

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

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

Results Point of Contact

Name/Title Boehringer Ingelheim Call Center
Organization Boehringer Ingelheim Pharmaceuticals
Phone 1-800-243-0127
Email clintriage.rdg@boehringer-ingelheim.com
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00998296
Other Study ID Numbers:
  • 1239.14
  • 2009-011321-14
First Posted:
Oct 20, 2009
Last Update Posted:
Aug 19, 2015
Last Verified:
Jul 1, 2015