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A Study of Intermittent, High-dose Afatinib to Determine the Maximal Tolerated Dose and Assess Activity of This Dose Against Non-small Cell Lung Cancer With T790M Mutations

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01647711
Recruitment Status : Completed
First Posted : July 23, 2012
Results First Posted : January 31, 2017
Last Update Posted : January 31, 2017
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Carcinoma, Non-Small-Cell Lung
Intervention Drug: Dose escalation followed by treatment with MTD
Enrollment 35
Recruitment Details  
Pre-assignment Details Afatinib was administered until disease progression, however patients experiencing clinical benefit were allowed to continue treatment for as long as judged beneficial by the investigator.
Arm/Group Title Afatinib 90mg Afatinib 120mg Afatinib 150mg Afatinib 160mg Afatinib 200mg
Hide Arm/Group Description Patients received oral administration of afatinib 90mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 120mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 150mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 160mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 200mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Period Title: Overall Study
Started 6 3 9 11 6
Completed 0 0 0 0 0
Not Completed 6 3 9 11 6
Reason Not Completed
Progressive disease             6             2             6             8             2
Other adverse event             0             0             2             0             2
Protocol Violation             0             0             0             0             1
Refused to continue taking medication             0             0             0             2             1
Other reason not defined             0             1             1             1             0
Arm/Group Title Afatinib 90mg Afatinib 120mg Afatinib 150mg Afatinib 160mg Afatinib 200mg Total
Hide Arm/Group Description Patients received oral administration of afatinib 90mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 120mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 150mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 160mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 200mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Total of all reporting groups
Overall Number of Baseline Participants 6 3 9 11 6 35
Hide Baseline Analysis Population Description
Treated set which included all patients who took at least one dose of afatinib.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 6 participants 3 participants 9 participants 11 participants 6 participants 35 participants
65.0
(64 to 80)
58.0
(50 to 77)
65.0
(54 to 77)
61.0
(45 to 70)
62.5
(54 to 75)
64.0
(45 to 80)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 3 participants 9 participants 11 participants 6 participants 35 participants
Female
2
  33.3%
1
  33.3%
6
  66.7%
10
  90.9%
5
  83.3%
24
  68.6%
Male
4
  66.7%
2
  66.7%
3
  33.3%
1
   9.1%
1
  16.7%
11
  31.4%
1.Primary Outcome
Title Percentage of Participants With Dose Limiting Toxicities
Hide Description Percentage of participants with Dose Limiting Toxicities (DLTs), based on investigator assessment, for determination of Maximum Tolerated Dose (MTD). MTD was defined as the dose in which less than 2 of up to 6 patients developed a DLT.
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set including patients eligible for MTD determination
Arm/Group Title Afatinib 90mg Afatinib 120mg Afatinib 150mg Afatinib 160mg Afatinib 200mg
Hide Arm/Group Description:
Patients received oral administration of afatinib 90mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 120mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 150mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 160mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 200mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Overall Number of Participants Analyzed 6 3 7 9 5
Measure Type: Number
Unit of Measure: Percentage of participants
16.7 0.0 0.0 0.0 40.0
2.Primary Outcome
Title Maximum Tolerated Dose
Hide Description Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT).
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set including patients eligible for MTD determination
Arm/Group Title Afatinib
Hide Arm/Group Description:
Patients receiving oral administration of afatinib film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Overall Number of Participants Analyzed 30
Measure Type: Number
Unit of Measure: mg
160
3.Secondary Outcome
Title Objective Response Rate for Patients With EGFR T790M Mutations
Hide Description

Objective response rate for patients with Epidermal Growth Factor Receptor (EGFR) T790M mutations. Objective response was defined as Complete Response (CR): Disappearance of all target lesion or Partial Response and (PR): >=30% decrease in the sum of the longest diameter of target lesions, according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

This endpoint was originally planned to be analysed in part B of the study, however as no participants were treated in part B the analysis was performed on the part A participants.
Time Frame From first drug administration until last drug administration, up to 420 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set including participants with EGFR T790M positive mutations
Arm/Group Title Afatinib 90mg Afatinib 120mg Afatinib 150mg Afatinib 160mg Afatinib 200mg
Hide Arm/Group Description:
Patients received oral administration of afatinib 90mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 120mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 150mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 160mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 200mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Overall Number of Participants Analyzed 1 0 7 1 4
Measure Type: Number
Unit of Measure: Percentage of participants
0.0 14.3 0.0 0.0
4.Secondary Outcome
Title Cmax of Afatinib on Day 3 of Course 1
Hide Description Maximum measured concentration (Cmax) of afatinib as determined on day 3 of course 1 for patients in Part A
Time Frame 47 hours (h) 55 minutes (min), 49h, 50h, 51h, 52h, 53h, 54h, 55h after first dose administration (on day 3 of course 1)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic set which included all patients treated in part A who were documented to have taken at least one dose of afatinib and who had in addition at least one valid afatinib concentration available.
Arm/Group Title Afatinib 90mg Afatinib 120mg Afatinib 150mg Afatinib 160mg Afatinib 200mg
Hide Arm/Group Description:
Patients received oral administration of afatinib 90mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 120mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 150mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 160mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Patients received oral administration of afatinib 200mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Overall Number of Participants Analyzed 6 3 8 8 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
129
(46.2%)
155
(86.9%)
311
(58.8%)
313
(35.6%)
461
(50.3%)
5.Secondary Outcome
Title Determination of Dosage for Expansion Cohort in Part B
Hide Description Determination of dosage for expansion cohort in Part B. Dosage was the MTD or less depending on tolerability.
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set including patients eligible for MTD determination
Arm/Group Title Afatinib
Hide Arm/Group Description:
Patients receiving oral administration of afatinib film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle.
Overall Number of Participants Analyzed 30
Measure Type: Number
Unit of Measure: mg
150
Time Frame From first treatment administration until 28 days after the last administration, up to 448 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Afatinib 90mg Afatinib 120mg Afatinib 150mg Afatinib 160mg Afatinib 200mg All Participants
Hide Arm/Group Description Patients received oral administration of afatinib 90mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 120mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 150mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 160mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. Patients received oral administration of afatinib 200mg film-coated tablet once daily for three days, repeated every 14 days, during each 28-day cycle. All treated participants included in the study.
All-Cause Mortality
Afatinib 90mg Afatinib 120mg Afatinib 150mg Afatinib 160mg Afatinib 200mg All Participants
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
Afatinib 90mg Afatinib 120mg Afatinib 150mg Afatinib 160mg Afatinib 200mg All Participants
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/6 (16.67%)   1/3 (33.33%)   7/9 (77.78%)   4/11 (36.36%)   1/6 (16.67%)   14/35 (40.00%) 
Gastrointestinal disorders             
Abdominal pain † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Diarrhoea † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Haematemesis † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Small intestinal obstruction † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  2/11 (18.18%)  0/6 (0.00%)  2/35 (5.71%) 
Hepatobiliary disorders             
Cholecystitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Infections and infestations             
Influenza † 1  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Urosepsis † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Metabolism and nutrition disorders             
Dehydration † 1  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%)  0/11 (0.00%)  0/6 (0.00%)  2/35 (5.71%) 
Hypokalaemia † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Malignant neoplasm progression † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  1/11 (9.09%)  0/6 (0.00%)  2/35 (5.71%) 
Nervous system disorders             
Aphasia † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Paraesthesia † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Respiratory, thoracic and mediastinal disorders             
Hypoxia † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  1/6 (16.67%)  2/35 (5.71%) 
Skin and subcutaneous tissue disorders             
Rash † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Vascular disorders             
Deep vein thrombosis † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Afatinib 90mg Afatinib 120mg Afatinib 150mg Afatinib 160mg Afatinib 200mg All Participants
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/6 (100.00%)   3/3 (100.00%)   9/9 (100.00%)   11/11 (100.00%)   6/6 (100.00%)   35/35 (100.00%) 
Blood and lymphatic system disorders             
Anaemia † 1  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%)  1/11 (9.09%)  0/6 (0.00%)  3/35 (8.57%) 
Neutropenia † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Cardiac disorders             
Sinus tachycardia † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Eye disorders             
Blepharitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Blindness † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Dry eye † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  1/11 (9.09%)  2/6 (33.33%)  4/35 (11.43%) 
Eyelid margin crusting † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Gastrointestinal disorders             
Abdominal distension † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Abdominal pain † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  2/35 (5.71%) 
Abdominal pain upper † 1  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Aphthous ulcer † 1  2/6 (33.33%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  2/35 (5.71%) 
Constipation † 1  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%)  3/11 (27.27%)  0/6 (0.00%)  5/35 (14.29%) 
Diarrhoea † 1  5/6 (83.33%)  2/3 (66.67%)  7/9 (77.78%)  11/11 (100.00%)  6/6 (100.00%)  31/35 (88.57%) 
Dry mouth † 1  0/6 (0.00%)  1/3 (33.33%)  4/9 (44.44%)  0/11 (0.00%)  0/6 (0.00%)  5/35 (14.29%) 
Eructation † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Gastrointestinal tract irritation † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Nausea † 1  2/6 (33.33%)  0/3 (0.00%)  5/9 (55.56%)  5/11 (45.45%)  4/6 (66.67%)  16/35 (45.71%) 
Oral discomfort † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Oral pain † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  2/35 (5.71%) 
Proctalgia † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Retching † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Stomatitis † 1  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%)  0/11 (0.00%)  2/6 (33.33%)  4/35 (11.43%) 
Vomiting † 1  1/6 (16.67%)  0/3 (0.00%)  3/9 (33.33%)  5/11 (45.45%)  4/6 (66.67%)  13/35 (37.14%) 
General disorders             
Asthenia † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Catheter site ulcer † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Chills † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  1/11 (9.09%)  0/6 (0.00%)  2/35 (5.71%) 
Fatigue † 1  3/6 (50.00%)  1/3 (33.33%)  5/9 (55.56%)  7/11 (63.64%)  2/6 (33.33%)  18/35 (51.43%) 
Gait disturbance † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Mucosal inflammation † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  7/11 (63.64%)  1/6 (16.67%)  9/35 (25.71%) 
Oedema peripheral † 1  1/6 (16.67%)  0/3 (0.00%)  2/9 (22.22%)  1/11 (9.09%)  1/6 (16.67%)  5/35 (14.29%) 
Pyrexia † 1  2/6 (33.33%)  0/3 (0.00%)  2/9 (22.22%)  0/11 (0.00%)  0/6 (0.00%)  4/35 (11.43%) 
Infections and infestations             
Candida infection † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Clostridium difficile infection † 1  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  2/35 (5.71%) 
Conjunctivitis † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  1/6 (16.67%)  2/35 (5.71%) 
Enterobacter bacteraemia † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Escherichia bacteraemia † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Oral candidiasis † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Oral herpes † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Pneumonia † 1  0/6 (0.00%)  1/3 (33.33%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  2/35 (5.71%) 
Sinusitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Skin candida † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Upper respiratory tract infection † 1  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  2/35 (5.71%) 
Urinary tract infection † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  3/11 (27.27%)  2/6 (33.33%)  6/35 (17.14%) 
Injury, poisoning and procedural complications             
Contusion † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Tooth fracture † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Urinary tract stoma complication † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Investigations             
Alanine aminotransferase increased † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  2/6 (33.33%)  3/35 (8.57%) 
Aspartate aminotransferase increased † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  2/6 (33.33%)  3/35 (8.57%) 
Blood alkaline phosphatase increased † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  1/6 (16.67%)  2/35 (5.71%) 
Blood creatinine increased † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  3/11 (27.27%)  0/6 (0.00%)  4/35 (11.43%) 
Breath sounds abnormal † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Electrocardiogram QT prolonged † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Gamma-glutamyltransferase increased † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  1/6 (16.67%)  2/35 (5.71%) 
Weight decreased † 1  3/6 (50.00%)  0/3 (0.00%)  3/9 (33.33%)  2/11 (18.18%)  1/6 (16.67%)  9/35 (25.71%) 
White blood cells urine positive † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Metabolism and nutrition disorders             
Decreased appetite † 1  1/6 (16.67%)  0/3 (0.00%)  4/9 (44.44%)  4/11 (36.36%)  3/6 (50.00%)  12/35 (34.29%) 
Dehydration † 1  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%)  2/11 (18.18%)  0/6 (0.00%)  4/35 (11.43%) 
Hypercalcaemia † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Hyperkalaemia † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Hypoalbuminaemia † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  1/6 (16.67%)  2/35 (5.71%) 
Hypocalcaemia † 1  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%)  0/11 (0.00%)  0/6 (0.00%)  2/35 (5.71%) 
Hypokalaemia † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  2/11 (18.18%)  0/6 (0.00%)  3/35 (8.57%) 
Hypomagnesaemia † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  1/6 (16.67%)  2/35 (5.71%) 
Hyponatraemia † 1  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%)  2/11 (18.18%)  0/6 (0.00%)  4/35 (11.43%) 
Hypophosphataemia † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Metabolic acidosis † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Musculoskeletal and connective tissue disorders             
Arthralgia † 1  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  1/6 (16.67%)  3/35 (8.57%) 
Back pain † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  2/6 (33.33%)  3/35 (8.57%) 
Bone pain † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Muscle spasms † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Muscle tightness † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Muscular weakness † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Musculoskeletal chest pain † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Musculoskeletal pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Pain in extremity † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  2/11 (18.18%)  2/6 (33.33%)  4/35 (11.43%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Malignant melanoma † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Malignant neoplasm progression † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Tumour pain † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Nervous system disorders             
Balance disorder † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Dizziness † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  1/11 (9.09%)  0/6 (0.00%)  2/35 (5.71%) 
Dysgeusia † 1  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%)  1/11 (9.09%)  2/6 (33.33%)  5/35 (14.29%) 
Headache † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Neuropathy peripheral † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  1/6 (16.67%)  2/35 (5.71%) 
Peripheral sensorimotor neuropathy † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Restless legs syndrome † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Syncope † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Tremor † 1  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Psychiatric disorders             
Anxiety † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  1/11 (9.09%)  0/6 (0.00%)  2/35 (5.71%) 
Confusional state † 1  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%)  0/11 (0.00%)  0/6 (0.00%)  2/35 (5.71%) 
Depression † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Insomnia † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Sleep disorder † 1  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Renal and urinary disorders             
Dysuria † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Haematuria † 1  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  2/35 (5.71%) 
Urinary incontinence † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Reproductive system and breast disorders             
Dyspareunia † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Vulval haemorrhage † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Vulvovaginal discomfort † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Vulvovaginal dryness † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Respiratory, thoracic and mediastinal disorders             
Cough † 1  0/6 (0.00%)  1/3 (33.33%)  2/9 (22.22%)  0/11 (0.00%)  0/6 (0.00%)  3/35 (8.57%) 
Dyspnoea † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Dyspnoea exertional † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Epistaxis † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Hypoxia † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  2/35 (5.71%) 
Oropharyngeal pain † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Pneumonitis † 1  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  2/35 (5.71%) 
Productive cough † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Rales † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Rhinorrhoea † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  1/6 (16.67%)  2/35 (5.71%) 
Wheezing † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Skin and subcutaneous tissue disorders             
Dermatitis acneiform † 1  2/6 (33.33%)  0/3 (0.00%)  2/9 (22.22%)  2/11 (18.18%)  0/6 (0.00%)  6/35 (17.14%) 
Dry skin † 1  0/6 (0.00%)  0/3 (0.00%)  3/9 (33.33%)  3/11 (27.27%)  1/6 (16.67%)  7/35 (20.00%) 
Erythema † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Nail bed tenderness † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  1/6 (16.67%)  1/35 (2.86%) 
Palmar-plantar erythrodysaesthesia syndrome † 1  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  1/35 (2.86%) 
Pruritus † 1  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  2/35 (5.71%) 
Rash † 1  4/6 (66.67%)  2/3 (66.67%)  3/9 (33.33%)  4/11 (36.36%)  4/6 (66.67%)  17/35 (48.57%) 
Skin reaction † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Surgical and medical procedures             
Sinus operation † 1  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%)  0/11 (0.00%)  0/6 (0.00%)  1/35 (2.86%) 
Vascular disorders             
Hypotension † 1  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%)  1/11 (9.09%)  0/6 (0.00%)  2/35 (5.71%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.1
One patient was screened in part B of the study, the patient did not meet eligibility requirements and was not treated. The trial completed enrollment in Part A before any additional patients were screened for Part B.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01647711    
Other Study ID Numbers: 1200.121
First Submitted: July 16, 2012
First Posted: July 23, 2012
Results First Submitted: September 22, 2016
Results First Posted: January 31, 2017
Last Update Posted: January 31, 2017