Afatinib and Vinorelbine in Tumours Known to Overexpress EGFR and/or HER2
Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT00906698
Collaborator
(none)
55
2
2
43
27.5
0.6
Study Details
Study Description
Brief Summary
To determine the maximum tolerated dose, safety, pharmacokinetics and anti-tumour efficacy of oral BIBW 2992 in combination with intravenous or oral vinorelbine
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
55 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I Open Label Trial to Assess Safety of BIBW 2992 With Vinorelbine in Solid Tumors Known to Overexpress HER2 and/or EGFR
Study Start Date
:
Jun 1, 2009
Actual Primary Completion Date
:
Jan 1, 2013
Actual Study Completion Date
:
Jan 1, 2013
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: BIBW 2992 and vinorelbine i.v Daily low (20mg), medium (40mg) and high (50mg) dosages of BIBW 2992 with standard dosage of vinorelbine i.v. |
Drug: BIBW 2992 low (20mg) dosage
Patients will receive 20mg dosage per day of BIBW 2992 plus standard dosage of vinorelbine.
Drug: BIBW 2992 medium (40mg) dosage
Patients will receive 40mg dosage per day of BIBW 2992 plus standard dosage of vinorelbine.
Drug: BIBW 2992 high (50mg) dosage
Patients will receive 50mg dosage of BIBW 2992 plus standard dosage of vinorelbine.
Drug: Vinorelbine i.v. 25 mg/m²
Patients will receive 25 mg/m² of Vinorelbine i.v.
|
| Experimental: BIBW 2992 and vinorelbine per os Daily low (20mg), medium (40mg) and high (50mg) dosages of BIBW 2992 with standard dosage of vinorelbine per os. |
Drug: BIBW 2992 low (20mg) dosage
Patients will receive 20mg dosage per day of BIBW 2992 plus standard dosage of vinorelbine.
Drug: BIBW 2992 medium (40mg) dosage
Patients will receive 40mg dosage per day of BIBW 2992 plus standard dosage of vinorelbine.
Drug: BIBW 2992 high (50mg) dosage
Patients will receive 50mg dosage of BIBW 2992 plus standard dosage of vinorelbine.
Drug: Vinorelbine per os 60 mg/m²
Patients will receive 60 mg/m² Vinorelbine per os at J1 J8 and J15
Drug: Vinorelbine per os 80 mg/m²
Patients will receive 80 mg/m² Vinorelbine per os at J22
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Dose-limiting Toxicities (DLT) [28 days]
Number of participants with DLT for the determination of the Maximum Tolerated Dose (MTD). 3+3 dose escalation design. MTD based on DLTs during first treatment course. After MTD was determined, additional patients were included at the MTD in an expansion cohort.
Secondary Outcome Measures
- Number of Patients With Best Overall Response [From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.]
Overall response is defined as complete response, partial response and stable disease and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0). Complete response (CR) and partial response (PR) had to be confirmed by a subsequent tumour assessment at least 28 days after the criteria for CR or PR were first met. To confirm a status of stable disease, the duration of stable disease was to be at least 42 days.
- Number of Patients With Objective Response (OR) [From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.]
OR is defined as confirmed complete response and confirmed partial response (PR) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0).
- Number of Patients With Disease Control (DC) [From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.]
DC is defined as confirmed complete response (CR), partial response (PR) and stable disease (SD) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0).
- Time to Objective Response [From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.]
The time to OR was the duration from the first treatment to the time when the measurement criteria for first documented confirmed CR and/or PR were met according to RECIST 1.0 criteria.
- Duration of Objective Response [From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.]
The duration of objective response was measured from the time of first documented confirmed CR or PR to the time of progressive disease or death, whichever occured earlier.
- Duration of Disease Control [From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter.]
Duration of disease control was measured from the start of study treatment to the time of progression or death, whichever occured first.
- Best Percentage Change in Tumour Size [Screening and every 8 weeks after starting of treatment, up to 44 weeks.]
Best percentage change in tumour size was the best percentage change in the sum of diameters of target lesions and was calculated as (minimum sum of diameters post baseline - sum of diameters at baseline)/sum of diameters at baseline. Negative values indicate a decrease, positive values an increase.
- Progression-free Survival (PFS) [From first dose of study medication to the occurrence of progression or death whichever came first, up to 44 months.]
PFS was defined as the time from the first dose of study medication to the occurrence of tumour progression or death, whichever came first. It was assessed according to RECIST 1.0. Median time results from unstratified Kaplan-Meier estimates.
- Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State [0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing]
- Area Under the Concentration-time Curve of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State [0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing]
- Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State [0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing]
- Maximum Measured Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25 mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State [0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing]
- Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State [0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing]
- Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State [0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing]
- Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State [0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h,, 7h and 24h after dosing]
- Area Under the Concentration-time Curve of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State [0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing]
- Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 Per os Vinorelbine at Steady State [0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing]
- Maximum Measured Concentration of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 in Presence and Absence of Afatinib at Steady State [0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing]
- Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State [0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing]
- Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Administrations of 60mg/m^2 Vinorelbine Per os in Presence and Absence of Afatinib at Steady State [0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing]
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion criteria:
-
Histologically or cytologically confirmed diagnosis of malignancy that is now advanced, non resectable and/or metastatic
-
Tumours historically known to overexpress EGFR and/or HER2
Exclusion criteria:
-
Prior treatment with HER2 inhibiting drugs within the past 4 weeks before the start of therapy or concomitantly with this trial.
-
Prior treatment with EGFR inhibiting drugs within the past two weeks before the start of therapy or concomitantly with this trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | 1200.69.3301 Boehringer Ingelheim Investigational Site | Toulouse Cedex | France | ||
| 2 | 1200.69.3302 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:
NCT00906698
Other Study ID Numbers:
- 1200.69
- 2008-006290-32
First Posted:
May 21, 2009
Last Update Posted:
Jun 9, 2014
Last Verified:
Mar 1, 2014
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os |
|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity . | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Period Title: Overall Study | ||||||
| STARTED | 3 | 19 | 6 | 4 | 18 | 5 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 3 | 19 | 6 | 4 | 18 | 5 |
Baseline Characteristics
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os | Total |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Total of all reporting groups |
| Overall Participants | 3 | 19 | 6 | 4 | 18 | 5 | 55 |
| Age (years) [Mean (Standard Deviation) ] | |||||||
| Mean (Standard Deviation) [years] |
59.7
(15.3)
|
55.3
(8.0)
|
61.7
(5.0)
|
55.3
(6.2)
|
50.9
(9.5)
|
51.0
(8.3)
|
54.4
(9.0)
|
| Sex: Female, Male (Count of Participants) | |||||||
| Female |
1
33.3%
|
11
57.9%
|
4
66.7%
|
0
0%
|
11
61.1%
|
4
80%
|
31
56.4%
|
| Male |
2
66.7%
|
8
42.1%
|
2
33.3%
|
4
100%
|
7
38.9%
|
1
20%
|
24
43.6%
|
Outcome Measures
| Title | Number of Participants With Dose-limiting Toxicities (DLT) |
|---|---|
| Description | Number of participants with DLT for the determination of the Maximum Tolerated Dose (MTD). 3+3 dose escalation design. MTD based on DLTs during first treatment course. After MTD was determined, additional patients were included at the MTD in an expansion cohort. |
| Time Frame | 28 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Treated Set (TS). TS consisted of all patients who were dispensed study medication and have taken at least 1 dose of Afatinib. |
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os |
|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Measure Participants | 3 | 19 | 6 | 4 | 18 | 5 |
| First cycle (N=3;6;6;4;6;5) |
0
0%
|
1
5.3%
|
4
66.7%
|
0
0%
|
1
5.6%
|
3
60%
|
| Expansion cohort (N=0;13;0;0;12;0) |
NA
NaN
|
7
36.8%
|
NA
NaN
|
NA
NaN
|
2
11.1%
|
NA
NaN
|
| Title | Number of Patients With Best Overall Response |
|---|---|
| Description | Overall response is defined as complete response, partial response and stable disease and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0). Complete response (CR) and partial response (PR) had to be confirmed by a subsequent tumour assessment at least 28 days after the criteria for CR or PR were first met. To confirm a status of stable disease, the duration of stable disease was to be at least 42 days. |
| Time Frame | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients from the Treated Set (TS). |
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os |
|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Measure Participants | 3 | 19 | 6 | 4 | 18 | 5 |
| Complete response |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Partial response |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
3
16.7%
|
0
0%
|
| Stable disease |
1
33.3%
|
10
52.6%
|
5
83.3%
|
0
0%
|
6
33.3%
|
5
100%
|
| Progressive disease |
2
66.7%
|
6
31.6%
|
0
0%
|
4
100%
|
7
38.9%
|
0
0%
|
| Missing |
0
0%
|
3
15.8%
|
1
16.7%
|
0
0%
|
2
11.1%
|
0
0%
|
| Title | Number of Patients With Objective Response (OR) |
|---|---|
| Description | OR is defined as confirmed complete response and confirmed partial response (PR) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0). |
| Time Frame | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients from the Treated Set (TS). |
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os |
|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Measure Participants | 3 | 19 | 6 | 4 | 18 | 5 |
| Number [participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
3
16.7%
|
0
0%
|
| Title | Number of Patients With Disease Control (DC) |
|---|---|
| Description | DC is defined as confirmed complete response (CR), partial response (PR) and stable disease (SD) and was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST 1.0). |
| Time Frame | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients from the Treated Set (TS). |
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os |
|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Measure Participants | 3 | 19 | 6 | 4 | 18 | 5 |
| Number [participants] |
1
33.3%
|
10
52.6%
|
5
83.3%
|
0
0%
|
9
50%
|
5
100%
|
| Title | Time to Objective Response |
|---|---|
| Description | The time to OR was the duration from the first treatment to the time when the measurement criteria for first documented confirmed CR and/or PR were met according to RECIST 1.0 criteria. |
| Time Frame | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients from the Treated Set (TS) with objective response. |
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os |
|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Measure Participants | 0 | 0 | 0 | 0 | 3 | 0 |
| Median (Full Range) [days] |
55
|
| Title | Duration of Objective Response |
|---|---|
| Description | The duration of objective response was measured from the time of first documented confirmed CR or PR to the time of progressive disease or death, whichever occured earlier. |
| Time Frame | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients from Treated Set (TS) with Objective Response. |
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os |
|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Measure Participants | 0 | 0 | 0 | 0 | 3 | 0 |
| Median (Full Range) [days] |
114
|
| Title | Duration of Disease Control |
|---|---|
| Description | Duration of disease control was measured from the start of study treatment to the time of progression or death, whichever occured first. |
| Time Frame | From first dose of study medication to response measurement, up to 44 months. Tumour assessments were performed at screening, week 8, week 16, week 24, and every 8 weeks thereafter. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients from Treated Set (TS) with disease control. |
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os |
|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Measure Participants | 1 | 10 | 5 | 0 | 9 | 5 |
| Median (Full Range) [days] |
110
|
167
|
168
|
162
|
120
|
| Title | Best Percentage Change in Tumour Size |
|---|---|
| Description | Best percentage change in tumour size was the best percentage change in the sum of diameters of target lesions and was calculated as (minimum sum of diameters post baseline - sum of diameters at baseline)/sum of diameters at baseline. Negative values indicate a decrease, positive values an increase. |
| Time Frame | Screening and every 8 weeks after starting of treatment, up to 44 weeks. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients from Treated Set (TS). |
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os |
|---|---|---|---|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Measure Participants | 3 | 19 | 6 | 4 | 18 | 5 |
| Mean (Standard Error) [percentage change in tumour size] |
-5.65
(10.91)
|
-7.51
(4.22)
|
-24.10
(9.57)
|
25.89
(4.55)
|
-1.36
(9.62)
|
-10.76
(3.47)
|
| Title | Progression-free Survival (PFS) |
|---|---|
| Description | PFS was defined as the time from the first dose of study medication to the occurrence of tumour progression or death, whichever came first. It was assessed according to RECIST 1.0. Median time results from unstratified Kaplan-Meier estimates. |
| Time Frame | From first dose of study medication to the occurrence of progression or death whichever came first, up to 44 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the MTD cohorts. |
| Arm/Group Title | Afatinib 40mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine Per os |
|---|---|---|
| Arm/Group Description | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity. |
| Measure Participants | 19 | 18 |
| Median (Inter-Quartile Range) [weeks] |
14.6
|
15.9
|
| Title | Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Vinorelbine i.v. | in Absence of Vinorelbine i.v. |
|---|---|---|
| Arm/Group Description | Afatinib 40 mg in presence of 25mg/m^2 vinorelbine i.v. | Afatinib 40 mg in absence of 25mg/m^2 vinorelbine i.v. |
| Measure Participants | 14 | 8 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
892
(87.3)
|
683
(375.0)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Afatinib 20mg With Vinorelbine i.v., Afatinib 40mg With Vinorelbine i.v. |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of adjusted gMean |
| Estimated Value | 126.20 | |
| Confidence Interval |
(2-Sided) 90% 69.549 to 229.012 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Area Under the Concentration-time Curve of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the TS, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Afatinib | in Absence of Afatinib |
|---|---|---|
| Arm/Group Description | 25mg/m^2 vinorelbine i.v. in presence of Afatinib 20, 40 and 50 mg | 25mg/m^2 vinorelbine i.v. in absence of Afatinib 20, 40 or 50 mg |
| Measure Participants | 12 | 18 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
512
(41.4)
|
655
(26.0)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Afatinib 20mg With Vinorelbine i.v., Afatinib 40mg With Vinorelbine i.v. |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of adjusted gMean |
| Estimated Value | 75.58 | |
| Confidence Interval |
(2-Sided) 90% 65.037 to 87.837 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Vinorelbine i.v. | in Absence of Vinorelbine i.v. |
|---|---|---|
| Arm/Group Description | Afatinib 40 mg in presence of 25mg/m^2 vinorelbine i.v. | Afatinib 40 mg in absence of 25mg/m^2 vinorelbine i.v. |
| Measure Participants | 14 | 8 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
62.0
(97.9)
|
42.7
(425)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Afatinib 20mg With Vinorelbine i.v., Afatinib 40mg With Vinorelbine i.v. |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of adjusted gMean |
| Estimated Value | 132.80 | |
| Confidence Interval |
(2-Sided) 90% 72.305 to 243.917 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Maximum Measured Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25 mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the TS, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Afatinib | in Absence of Afatinib |
|---|---|---|
| Arm/Group Description | 25mg/m^2 vinorelbine i.v. in presence of Afatinib 20, 40 and 50mg Afatinib | 25mg/m^2 vinorelbine i.v. in absence of Afatinib 20, 40 and 50mg Afatinib |
| Measure Participants | 12 | 18 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
822
(56.2)
|
941
(55.1)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Afatinib 20mg With Vinorelbine i.v., Afatinib 40mg With Vinorelbine i.v. |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of adjusted gMean |
| Estimated Value | 83.80 | |
| Confidence Interval |
(2-Sided) 90% 61.156 to 114.823 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 i.v. Vinorelbine at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Vinorelbine i.v. | in Absence of Vinorelbine i.v. |
|---|---|---|
| Arm/Group Description | Afatinib 40 mg in presence of 25mg/m^2 vinorelbine i.v. | Afatinib 40 mg in absence of 25mg/m^2 vinorelbine i.v. |
| Measure Participants | 14 | 8 |
| Median (Full Range) [hours] |
3.16
|
2.00
|
| Title | Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Intravenous Administrations of 25mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the TS, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Afatinib | in Absence of Afatinib |
|---|---|---|
| Arm/Group Description | 25mg/m^2 vinorelbine i.v. in presence of Afatinib 20, 40 and 50 mg | 25mg/m^2 vinorelbine i.v. in absence of Afatinib 20, 40 or 50 mg |
| Measure Participants | 12 | 18 |
| Median (Full Range) [hours] |
0.166
|
0.167
|
| Title | Area Under the Concentration-time Curve of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h,, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Vinorelbine Per os | in Absence of Vinorelbine Per os |
|---|---|---|
| Arm/Group Description | Afatinib 40 mg in presence of 60mg/m^2 vinorelbine per os. | Afatinib 40 mg in absence of 60mg/m^2 vinorelbine per os. |
| Measure Participants | 9 | 8 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
872
(39.8)
|
1070
(33.8)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Afatinib 20mg With Vinorelbine i.v., Afatinib 40mg With Vinorelbine i.v. |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of adjusted gMean |
| Estimated Value | 90.21 | |
| Confidence Interval |
(2-Sided) 90% 76.071 to 106.978 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Area Under the Concentration-time Curve of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 Vinorelbine in Presence and Absence of Afatinib at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the TS, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Afatinib | in Absence of Afatinib |
|---|---|---|
| Arm/Group Description | 60 mg/m^2 vinorelbine per os in presence of Afatinib | 60 mg/m^2 vinorelbine per os in absence of Afatinib |
| Measure Participants | 15 | 25 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
258
(79.8)
|
334
(70.9)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Afatinib 20mg With Vinorelbine i.v., Afatinib 40mg With Vinorelbine i.v. |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of adjusted gMean |
| Estimated Value | 76.75 | |
| Confidence Interval |
(2-Sided) 90% 56.710 to 103.871 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Maximum Measured Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 25mg/m^2 Per os Vinorelbine at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Vinorelbine Per os | in Absence of Vinorelbine Per os |
|---|---|---|
| Arm/Group Description | Afatinib 40 mg in presence of 25mg/m^2 vinorelbine per os | Afatinib 40 mg in absence of 25mg/m^2 vinorelbine per os |
| Measure Participants | 10 | 9 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
55.1
(35.6)
|
67.2
(29.4)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Afatinib 20mg With Vinorelbine i.v., Afatinib 40mg With Vinorelbine i.v. |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of adjusted gMean |
| Estimated Value | 83.86 | |
| Confidence Interval |
(2-Sided) 95% 66.369 to 105.966 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Maximum Measured Concentration of Vinorelbine After Multiple Administrations Per os of 60mg/m^2 in Presence and Absence of Afatinib at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 0.10h, 0.30h, 1h, 4h, 7h, 24h and 168h after dosing, 0.05 hours (h) before dosing at day 15 and day 21 and 0.10h, 0.30h, 1h, 2h, 3h, 4h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the TS, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Afatinib | in Absence of Afatinib |
|---|---|---|
| Arm/Group Description | 60mg/m^2 vinorelbine per os in presence of afatinib | 60mg/m^2 vinorelbine per os in absence of afatinib |
| Measure Participants | 15 | 25 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
52.8
(80.8)
|
65.0
(63.9)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Afatinib 20mg With Vinorelbine i.v., Afatinib 40mg With Vinorelbine i.v. |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of adjusted gMean |
| Estimated Value | 81.70 | |
| Confidence Interval |
(2-Sided) 90% 60.470 to 110.369 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Time From Dosing to the Maximum Concentration of Afatinib After Multiple Administrations of 40mg Afatinib in Presence and Absence of 60mg/m^2 Per os Vinorelbine at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the MTD cohort, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Vinorelbine Per os | in Absence of Vinorelbine Per os |
|---|---|---|
| Arm/Group Description | Afatinib 40 mg in presence of 60mg/m^2 vinorelbine per os | Afatinib 40 mg in absence of 60mg/m^2 vinorelbine per os |
| Measure Participants | 10 | 9 |
| Median (Full Range) [hours] |
3.54
|
3.00
|
| Title | Time From Dosing to the Maximum Concentration of Vinorelbine After Single and Multiple Administrations of 60mg/m^2 Vinorelbine Per os in Presence and Absence of Afatinib at Steady State |
|---|---|
| Description | |
| Time Frame | 0.05 hours (h) before dosing at day 1 and 1h, 1.30h, 2h, 3h, 6h, 7h and 24h after dosing |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients treated in the TS, for which evaluable PK parameters were available for the analysis. |
| Arm/Group Title | in Presence of Afatinib | in Absence of Afatinib |
|---|---|---|
| Arm/Group Description | 60mg/m^2 vinorelbine per os in presence of afatinib | 60mg/m^2 vinorelbine per os in absence of afatinib |
| Measure Participants | 15 | 25 |
| Median (Full Range) [hours] |
1.50
|
1.50
|
Adverse Events
| Time Frame | First administration of trial medication until 28 days after last administration of trial medication. | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||||||
| Arm/Group Title | Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os | ||||||
| Arm/Group Description | Continuous daily dosing of Afatinib 20mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity . | Continuous daily dosing of Afatinib 40mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity . | Continuous daily dosing of Afatinib 50mg orally and weekly Vinorelbine 25 mg/m2 intravenously (days 1, 8, 15 and 22) in a 4-weekly course. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity . | Continuous daily dosing of Afatinib 20mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity . | Continuous daily dosing of Afatinib 40mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity . | Continuous daily dosing of Afatinib 50mg orally and oral vinorelbine 60 mg/m2/week for days 1,8,15 of first cycle, and 80mg/m2 from day 22 first cycle onwards, weekly. Patients will be eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity . | ||||||
All Cause Mortality |
||||||||||||
| Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os | |||||||
| 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) | ||||||
Serious Adverse Events |
||||||||||||
| Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os | |||||||
| 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 | 1/3 (33.3%) | 11/19 (57.9%) | 4/6 (66.7%) | 2/4 (50%) | 13/18 (72.2%) | 1/5 (20%) | ||||||
| Blood and lymphatic system disorders | ||||||||||||
| Anaemia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Febrile neutropenia | 0/3 (0%) | 1/19 (5.3%) | 1/6 (16.7%) | 0/4 (0%) | 3/18 (16.7%) | 0/5 (0%) | ||||||
| Neutropenia | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Ear and labyrinth disorders | ||||||||||||
| Vertigo | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Diarrhoea | 0/3 (0%) | 3/19 (15.8%) | 1/6 (16.7%) | 0/4 (0%) | 2/18 (11.1%) | 1/5 (20%) | ||||||
| Gastrointestinal haemorrhage | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 1/4 (25%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Nausea | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Stomatitis | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Vomiting | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 2/18 (11.1%) | 1/5 (20%) | ||||||
| General disorders | ||||||||||||
| Asthenia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Chest pain | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| General physical health deterioration | 1/3 (33.3%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Mucosal inflammation | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Hepatobiliary disorders | ||||||||||||
| Hepatocellular injury | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Infections and infestations | ||||||||||||
| Biliary tract infection | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Bronchitis | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Lung infection | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Pneumonia | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Fall | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Femoral neck fracture | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Pneumothorax traumatic | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Investigations | ||||||||||||
| Lipase increased | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Weight decreased | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Metabolism and nutrition disorders | ||||||||||||
| Decreased appetite | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Dehydration | 0/3 (0%) | 2/19 (10.5%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hypercalcaemia | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hypokalaemia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Back pain | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Mobility decreased | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
| Metastases to meninges | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Nervous system disorders | ||||||||||||
| Aphasia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Convulsion | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hemianopia homonymous | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Intracranial pressure increased | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Paraesthesia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Psychiatric disorders | ||||||||||||
| Depression | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Renal and urinary disorders | ||||||||||||
| Renal failure | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Acute respiratory failure | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Dyspnoea | 0/3 (0%) | 3/19 (15.8%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Interstitial lung disease | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Pleural effusion | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Respiratory failure | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 1/4 (25%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Vascular disorders | ||||||||||||
| Orthostatic hypotension | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 1/4 (25%) | 0/18 (0%) | 0/5 (0%) | ||||||
Other (Not Including Serious) Adverse Events |
||||||||||||
| Afatinib 20mg With Vinorelbine i.v. | Afatinib 40mg With Vinorelbine i.v. | Afatinib 50mg With Vinorelbine i.v. | Afatinib 20mg With Vinorelbine Per os | Afatinib 40mg With Vinorelbine Per os | Afatinib 50mg With Vinorelbine Per os | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/3 (100%) | 19/19 (100%) | 6/6 (100%) | 4/4 (100%) | 18/18 (100%) | 5/5 (100%) | ||||||
| Blood and lymphatic system disorders | ||||||||||||
| Anaemia | 1/3 (33.3%) | 9/19 (47.4%) | 3/6 (50%) | 2/4 (50%) | 8/18 (44.4%) | 5/5 (100%) | ||||||
| Febrile neutropenia | 0/3 (0%) | 2/19 (10.5%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Leukocytosis | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Leukopenia | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Lymph node pain | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Lymphadenopathy | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Lymphopenia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 3/18 (16.7%) | 0/5 (0%) | ||||||
| Neutropenia | 2/3 (66.7%) | 12/19 (63.2%) | 3/6 (50%) | 1/4 (25%) | 8/18 (44.4%) | 4/5 (80%) | ||||||
| Thrombocytopenia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Thrombocytosis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Cardiac disorders | ||||||||||||
| Atrioventricular block | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Ear and labyrinth disorders | ||||||||||||
| Ear disorder | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hypoacusis | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Tinnitus | 0/3 (0%) | 1/19 (5.3%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Vertigo | 1/3 (33.3%) | 1/19 (5.3%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Eye disorders | ||||||||||||
| Blepharitis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Conjunctivitis | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Dry eye | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Exophthalmos | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Eyelid ptosis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Lacrimation increased | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 1/4 (25%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Ocular icterus | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Photopsia | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Visual acuity reduced | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Abdominal pain | 1/3 (33.3%) | 3/19 (15.8%) | 2/6 (33.3%) | 1/4 (25%) | 5/18 (27.8%) | 2/5 (40%) | ||||||
| Abdominal pain lower | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Abdominal pain upper | 1/3 (33.3%) | 5/19 (26.3%) | 1/6 (16.7%) | 1/4 (25%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Anal haemorrhage | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Anorectal discomfort | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Aphthous stomatitis | 0/3 (0%) | 4/19 (21.1%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 2/5 (40%) | ||||||
| Ascites | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Chapped lips | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Cheilitis | 0/3 (0%) | 0/19 (0%) | 2/6 (33.3%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Colitis | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Constipation | 1/3 (33.3%) | 7/19 (36.8%) | 2/6 (33.3%) | 2/4 (50%) | 7/18 (38.9%) | 2/5 (40%) | ||||||
| Diarrhoea | 3/3 (100%) | 19/19 (100%) | 6/6 (100%) | 2/4 (50%) | 17/18 (94.4%) | 5/5 (100%) | ||||||
| Dry mouth | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Dyspepsia | 2/3 (66.7%) | 1/19 (5.3%) | 1/6 (16.7%) | 1/4 (25%) | 3/18 (16.7%) | 1/5 (20%) | ||||||
| Dysphagia | 0/3 (0%) | 4/19 (21.1%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Gastritis | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Gastrointestinal haemorrhage | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Gastrointestinal toxicity | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Gastrooesophageal reflux disease | 1/3 (33.3%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 4/18 (22.2%) | 1/5 (20%) | ||||||
| Gingival bleeding | 1/3 (33.3%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Gingival pain | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Glossodynia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Haemorrhoids | 0/3 (0%) | 3/19 (15.8%) | 1/6 (16.7%) | 1/4 (25%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Melaena | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 1/4 (25%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Nausea | 0/3 (0%) | 12/19 (63.2%) | 5/6 (83.3%) | 3/4 (75%) | 11/18 (61.1%) | 4/5 (80%) | ||||||
| Odynophagia | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Oesophagitis | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Oral disorder | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Pancreatitis | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Portal hypertensive gastropathy | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Proctalgia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Rectal haemorrhage | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 1/4 (25%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Salivary hypersecretion | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Stomatitis | 2/3 (66.7%) | 7/19 (36.8%) | 2/6 (33.3%) | 0/4 (0%) | 7/18 (38.9%) | 2/5 (40%) | ||||||
| Tongue ulceration | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Vomiting | 0/3 (0%) | 8/19 (42.1%) | 4/6 (66.7%) | 1/4 (25%) | 13/18 (72.2%) | 3/5 (60%) | ||||||
| General disorders | ||||||||||||
| Asthenia | 2/3 (66.7%) | 19/19 (100%) | 6/6 (100%) | 4/4 (100%) | 14/18 (77.8%) | 5/5 (100%) | ||||||
| Catheter site pain | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Chest pain | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 2/5 (40%) | ||||||
| Chills | 1/3 (33.3%) | 0/19 (0%) | 0/6 (0%) | 1/4 (25%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Facial pain | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Fatigue | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Feeling cold | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| General physical health deterioration | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Hyperthermia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Inflammation | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Mucosal discolouration | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Mucosal inflammation | 0/3 (0%) | 8/19 (42.1%) | 4/6 (66.7%) | 0/4 (0%) | 6/18 (33.3%) | 2/5 (40%) | ||||||
| Oedema peripheral | 1/3 (33.3%) | 3/19 (15.8%) | 2/6 (33.3%) | 0/4 (0%) | 2/18 (11.1%) | 1/5 (20%) | ||||||
| Pain | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Puncture site pain | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Pyrexia | 1/3 (33.3%) | 10/19 (52.6%) | 2/6 (33.3%) | 2/4 (50%) | 6/18 (33.3%) | 2/5 (40%) | ||||||
| Ulcer | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Xerosis | 0/3 (0%) | 2/19 (10.5%) | 1/6 (16.7%) | 1/4 (25%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Hepatobiliary disorders | ||||||||||||
| Cholestasis | 0/3 (0%) | 3/19 (15.8%) | 0/6 (0%) | 1/4 (25%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Hepatocellular injury | 0/3 (0%) | 6/19 (31.6%) | 1/6 (16.7%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Jaundice cholestatic | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Infections and infestations | ||||||||||||
| Bronchitis | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Cystitis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Device related infection | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Ear infection | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Escherichia infection | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Escherichia urinary tract infection | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Folliculitis | 0/3 (0%) | 7/19 (36.8%) | 2/6 (33.3%) | 0/4 (0%) | 7/18 (38.9%) | 2/5 (40%) | ||||||
| Fungal infection | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Fungal oesophagitis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Fungal paronychia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Furuncle | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Gastroenteritis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Genital infection fungal | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Gingivitis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Herpes virus infection | 0/3 (0%) | 1/19 (5.3%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hordeolum | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Infection | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Lymphangitis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Nasopharyngitis | 0/3 (0%) | 3/19 (15.8%) | 2/6 (33.3%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Oesophageal candidiasis | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Oral fungal infection | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Oral herpes | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 2/5 (40%) | ||||||
| Otitis externa | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Paronychia | 0/3 (0%) | 5/19 (26.3%) | 2/6 (33.3%) | 0/4 (0%) | 5/18 (27.8%) | 3/5 (60%) | ||||||
| Pharyngitis | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Proteus infection | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Pulpitis dental | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Puncture site abscess | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Rash pustular | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Rhinitis | 0/3 (0%) | 6/19 (31.6%) | 3/6 (50%) | 0/4 (0%) | 4/18 (22.2%) | 1/5 (20%) | ||||||
| Sinusitis | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Staphylococcal infection | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Tinea pedis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Tooth abscess | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 0/5 (0%) | ||||||
| Upper respiratory fungal infection | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Urinary tract infection | 1/3 (33.3%) | 4/19 (21.1%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Urinary tract infection bacterial | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Urinary tract infection enterococcal | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Burn oesophageal | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Fall | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Investigations | ||||||||||||
| Amylase increased | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Aspartate aminotransferase increased | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Blood bilirubin increased | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Blood creatine phosphokinase increased | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Blood creatinine increased | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 1/5 (20%) | ||||||
| Blood phosphorus decreased | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Eastern Cooperative Oncology Group performance status worsened | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Weight decreased | 0/3 (0%) | 4/19 (21.1%) | 3/6 (50%) | 2/4 (50%) | 2/18 (11.1%) | 2/5 (40%) | ||||||
| White blood cell count increased | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 1/4 (25%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Metabolism and nutrition disorders | ||||||||||||
| Cell death | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Decreased appetite | 1/3 (33.3%) | 13/19 (68.4%) | 4/6 (66.7%) | 3/4 (75%) | 10/18 (55.6%) | 2/5 (40%) | ||||||
| Dehydration | 0/3 (0%) | 3/19 (15.8%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hyperglycaemia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hyperkalaemia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hyperproteinaemia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Hypoalbuminaemia | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Hypocalcaemia | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hypoglycaemia | 1/3 (33.3%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hypokalaemia | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 2/5 (40%) | ||||||
| Hypomagnesaemia | 1/3 (33.3%) | 5/19 (26.3%) | 3/6 (50%) | 0/4 (0%) | 5/18 (27.8%) | 1/5 (20%) | ||||||
| Hyponatraemia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 1/4 (25%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Arthralgia | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 1/4 (25%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Back pain | 0/3 (0%) | 4/19 (21.1%) | 0/6 (0%) | 0/4 (0%) | 4/18 (22.2%) | 0/5 (0%) | ||||||
| Bone pain | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Hypercreatinaemia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Muscle spasms | 0/3 (0%) | 5/19 (26.3%) | 3/6 (50%) | 0/4 (0%) | 4/18 (22.2%) | 2/5 (40%) | ||||||
| Musculoskeletal chest pain | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Musculoskeletal pain | 1/3 (33.3%) | 3/19 (15.8%) | 1/6 (16.7%) | 0/4 (0%) | 3/18 (16.7%) | 0/5 (0%) | ||||||
| Myalgia | 1/3 (33.3%) | 1/19 (5.3%) | 0/6 (0%) | 1/4 (25%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Neck pain | 0/3 (0%) | 2/19 (10.5%) | 1/6 (16.7%) | 1/4 (25%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Osteonecrosis of jaw | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Pain in jaw | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Sarcopenia | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
| Haemangioma of bone | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Nervous system disorders | ||||||||||||
| Aphonia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Balance disorder | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Burning sensation | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Cerebral microhaemorrhage | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Cervical root pain | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Dysaesthesia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Dysgeusia | 1/3 (33.3%) | 4/19 (21.1%) | 2/6 (33.3%) | 0/4 (0%) | 2/18 (11.1%) | 2/5 (40%) | ||||||
| Epilepsy | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Headache | 0/3 (0%) | 2/19 (10.5%) | 1/6 (16.7%) | 0/4 (0%) | 2/18 (11.1%) | 1/5 (20%) | ||||||
| Hydrocephalus | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hyperaesthesia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Neuralgia | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Neuropathy peripheral | 1/3 (33.3%) | 0/19 (0%) | 2/6 (33.3%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Paraesthesia | 0/3 (0%) | 4/19 (21.1%) | 5/6 (83.3%) | 1/4 (25%) | 5/18 (27.8%) | 1/5 (20%) | ||||||
| Sciatica | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Sensory loss | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Somnolence | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Syncope | 0/3 (0%) | 2/19 (10.5%) | 1/6 (16.7%) | 1/4 (25%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Toxic neuropathy | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Tremor | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Psychiatric disorders | ||||||||||||
| Anxiety | 0/3 (0%) | 1/19 (5.3%) | 2/6 (33.3%) | 2/4 (50%) | 4/18 (22.2%) | 3/5 (60%) | ||||||
| Depression | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 1/5 (20%) | ||||||
| Hallucination, visual | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Insomnia | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 2/4 (50%) | 2/18 (11.1%) | 1/5 (20%) | ||||||
| Sleep disorder | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Renal and urinary disorders | ||||||||||||
| Bladder discomfort | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Dysuria | 0/3 (0%) | 2/19 (10.5%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Micturition disorder | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Pollakiuria | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Proteinuria | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Renal failure | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Urinary incontinence | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Reproductive system and breast disorders | ||||||||||||
| Breast mass | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Breast pain | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Genital lesion | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Genital tract inflammation | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Scrotal oedema | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Vaginal haemorrhage | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Vulvovaginal burning sensation | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Vulvovaginal dryness | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Vulvovaginal pruritus | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Bronchial hyperreactivity | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Cough | 0/3 (0%) | 9/19 (47.4%) | 2/6 (33.3%) | 1/4 (25%) | 4/18 (22.2%) | 2/5 (40%) | ||||||
| Dysphonia | 0/3 (0%) | 5/19 (26.3%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Dyspnoea | 1/3 (33.3%) | 9/19 (47.4%) | 2/6 (33.3%) | 0/4 (0%) | 7/18 (38.9%) | 0/5 (0%) | ||||||
| Epistaxis | 0/3 (0%) | 6/19 (31.6%) | 4/6 (66.7%) | 0/4 (0%) | 4/18 (22.2%) | 2/5 (40%) | ||||||
| Haemoptysis | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Hiccups | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Increased bronchial secretion | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 1/4 (25%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Nasal dryness | 0/3 (0%) | 1/19 (5.3%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Nasal polyps | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Oropharyngeal pain | 0/3 (0%) | 1/19 (5.3%) | 2/6 (33.3%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Pharyngeal erythema | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Pneumothorax | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Pulmonary embolism | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Respiratory distress | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Rhinorrhoea | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 1/4 (25%) | 4/18 (22.2%) | 0/5 (0%) | ||||||
| Upper respiratory tract inflammation | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Skin and subcutaneous tissue disorders | ||||||||||||
| Acne | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Actinic keratosis | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Alopecia | 0/3 (0%) | 1/19 (5.3%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Dermatitis acneiform | 1/3 (33.3%) | 4/19 (21.1%) | 2/6 (33.3%) | 0/4 (0%) | 2/18 (11.1%) | 1/5 (20%) | ||||||
| Dry skin | 0/3 (0%) | 4/19 (21.1%) | 1/6 (16.7%) | 1/4 (25%) | 4/18 (22.2%) | 1/5 (20%) | ||||||
| Eczema | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Eczema asteatotic | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Erythema | 0/3 (0%) | 4/19 (21.1%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Hair colour changes | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hair texture abnormal | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Nail dystrophy | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Nail pigmentation | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Nail pitting | 0/3 (0%) | 1/19 (5.3%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Nail toxicity | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Night sweats | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 1/4 (25%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Onychoclasis | 0/3 (0%) | 2/19 (10.5%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Palmar erythema | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Palmar-plantar erythrodysaesthesia syndrome | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 1/5 (20%) | ||||||
| Pemphigoid | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Petechiae | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Pruritus | 0/3 (0%) | 3/19 (15.8%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Rash | 1/3 (33.3%) | 7/19 (36.8%) | 1/6 (16.7%) | 0/4 (0%) | 9/18 (50%) | 3/5 (60%) | ||||||
| Rash macular | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Rash papular | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Rash pruritic | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Skin fissures | 0/3 (0%) | 3/19 (15.8%) | 2/6 (33.3%) | 0/4 (0%) | 3/18 (16.7%) | 3/5 (60%) | ||||||
| Skin irritation | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Skin lesion | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Skin toxicity | 0/3 (0%) | 0/19 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Subcutaneous nodule | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Urticaria | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Xeroderma | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 2/18 (11.1%) | 1/5 (20%) | ||||||
| Vascular disorders | ||||||||||||
| Deep vein thrombosis | 1/3 (33.3%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Hypotension | 0/3 (0%) | 1/19 (5.3%) | 1/6 (16.7%) | 0/4 (0%) | 1/18 (5.6%) | 0/5 (0%) | ||||||
| Intermittent claudication | 0/3 (0%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 1/5 (20%) | ||||||
| Lymphoedema | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Orthostatic hypotension | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Pallor | 0/3 (0%) | 1/19 (5.3%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
| Thrombophlebitis superficial | 1/3 (33.3%) | 0/19 (0%) | 0/6 (0%) | 0/4 (0%) | 0/18 (0%) | 0/5 (0%) | ||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Results Point of Contact
| Name/Title | Boehringer Ingelheim Call Center |
|---|---|
| Organization | Boehringer Ingelheim Pharmaceuticals |
| Phone | 1-800-243-0127 |
| clintriage.rdg@boehringer-ingelheim.com |
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00906698
Other Study ID Numbers:
- 1200.69
- 2008-006290-32
First Posted:
May 21, 2009
Last Update Posted:
Jun 9, 2014
Last Verified:
Mar 1, 2014