BIBW 2992 and Letrozole in Hormonoresistant Metastatic Breast Cancer

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00708214
• Collaborator: (none)
• Enrollment: 28
• Locations: 5
• Arms: 2
• Patients Per Site: 5.6

Study Details

Study Description

Brief Summary

Progression-free rate after 16 weeks of BIBW 2992 administration in association with letrozole

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: BIBW 2992; Drug: BIBW 2992; Drug: Letrozole; Drug: Letrozole	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Non-Randomized
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of BIBW 2992 Administration in Patients With Hormone Refractory Metastatic Breast Cancer
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Feb 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BIBW 2992 To study BIBW 2992 in association with letrozole in hormonoresistant metastatic breast cancer	Drug: BIBW 2992; BIBW 2992 at high and medium dosages; Drug: Letrozole; Letrozole at standard dosage
Other: Letrozole Hormonotherapy for metastatic breast cancer	Drug: BIBW 2992; BIBW 2992 at high and medium dosages; Drug: Letrozole; Letrozole at standard dosage

Outcome Measures

Primary Outcome Measures

1. Percentage of Progression Free Participants After 16 Weeks of Treatment [16 weeks]

   Progression was defined according to 1 of the following criteria: New bone lesion(s) on bone scan or on magnetic resonance imaging; Progression or occurrence of new lesion(s) according to the Response Evaluation Criteria In Solid Tumours version 1.0 (RECIST); an increase in tumour marker CA 15.3 of more than 20 percent,compared with baseline, at 2 consecutive examinations; occurrence of disease-related skeletal events. If a patient did not fulfil any criteria and was withdrawn because of clinical deterioration amounting to PD according to the Investigator, they were considered as having PD.

Secondary Outcome Measures

1. Number of Participants With Confirmed Objective Response (OR) [Baseline till progression]

   OR was defined as complete response (CR) or partial response (PR) and was assessed according to RECIST criteria regardless of treatment status.

2. Number of Participants With Clinical Benefit (CB) [16 weeks and 24 weeks]

   CB was defined as CR, PR or stable disease (SD) and was assessed according to RECIST criteria regardless of treatment status.

3. Time to RECIST Tumour Reponse [Baseline till progression]

   The time to OR was the duration from the first treatment to the time when the measurement criteria for CR and/or PR were met according to RECIST criteria.

4. Duration of Confirmed OR [First occurence or OR till progression or death]

   Duration of confirmed OR is measured from the time of first OR to the time of progression or death (or date of censoring for progression free survival).

5. Progression-free Survival (PFS) [Baseline till progression, death or data cut-off (04 Jan 2010)]

   PFS was defined as the time from the first treatment to the occurrence of tumour progression or death, whichever came first. Progression was assessed according to RECIST criteria.

6. Overall Survival (OS) [Baseline till progression, death or data cut-off]

   OS was defined as the time from first treatment to death.

7. Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) [0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing]

   AUCtau,ss represents the area under the concentration curve of afatinib in plasma over a uniform dosing interval tau at steady state.

8. Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss) [0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing]

   Cmax,ss represents the maximum measured concentration of afatinib in plasma at steady state.

9. Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 57 (Cpre,ss,57) [Day 57]

   Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57.

10. Pre-dose Concentration of Afatinib in Plasma at Steady Stateon Day 85 (Cpre,ss,85) [Day 85]

    Cpre,ss,85 represents the pre-dose concentration of afatinib in plasma at steady state on day 85.

11. Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss) [0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing]

    tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state

12. Area Under Curve of Letrozole Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss) [0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing]

    AUC0-tau,ss represents the area under the concentration curve of letrozole in plasma over a uniform dosing interval tau at steady state.

13. Maximum Concentration of Letrozole in Plasma at Steady State (Cmax,ss) [0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing]

    Cmax,ss represents the maximum measured concentration of letrozole in plasma at steady state.

14. Time From Dosing to the Maximum Concentration of Letrozole in Plasma at Steady State (Tmax,ss) [0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing]

    tmax,ss represents the time from dosing to the maximum concentration of letrozole in plasma at steady state.

15. Change From Baseline in Ca15.3 [baseline and day 29]

    Change from baseline in Ca15.3 tumor marker levels

16. Best Change From Baseline in ECOG Performance Status [baseline till end of treatment]

    Best change from baseline in ECOG (Eastern Cooperative Oncology Group) performance status. ECOG is measured as score between 0 (fully active) and 5 (dead). Improvement is a decrease in ECOG score from baseline of at least 1. Deterioration is an increase in ECOG score from baseline of at least 1

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Female patients with histologically proven breast adenocarcinoma

• Presence of metastatic disease No more than 2 prior chemotherapy regimens for metastatic disease, which could include trastuzumab Patients must currently be on letrozole and developed acquired resistance as defined by disease progression on letrozole following previous response (partial response or better, stable disease superior or equal to 24 weeks)

Diagnosis of disease progression inferior or equal to 6 weeks prior to trial entrydefined as:

1. Increase in the number of bone lesions on bone scan or on MRI AND/OR

2. Increased pain in an area of known bony metastasis AND superior or equal to 2 serial elevations in CA 15.3 AND/OR

3. Progression according to RECIST criteria on CT scan, MRI, or x-ray Patients must have documented menopause confirmed by estradiol level inferior to 11 pg/ml

Exclusion criteria:

• Premenopausal patients

• Rapidly progressive disease in major organs (i.e. lymphangitic spread in the lung and/or bulky liver metastasis) Patient with brain metastasis Significant cardiovascular diseases Previous treatment with an EGFR and/or HER-2 inhibiting drug(patients who received trastuzumab with chemotherapy but not with letrozole can be enrolled)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1200.5.3306A Boehringer Ingelheim Investigational Site	Caen Cedex		France
2	1200.5.3304A Boehringer Ingelheim Investigational Site	Nice Cedex 2		France
3	1200.5.3301A Boehringer Ingelheim Investigational Site	Paris Cedex 10		France
4	1200.5.3305A Boehringer Ingelheim Investigational Site	Paris Cedex 20		France
5	1200.5.3302A Boehringer Ingelheim Investigational Site	Saint Cloud		France

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00708214
• Other Study ID Numbers: 1200.5; 2006-002814-37
• First Posted: Jul 2, 2008
• Last Update Posted: Dec 30, 2013
• Last Verified: Oct 1, 2013

• Additional relevant MeSH terms: Breast Neoplasms; Letrozole; Afatinib

Study Results

Participant Flow

Pre-assignment Detail	According to the protocol the starting dose of Afatinib was 50mg/day. This dose was reduced according to the protocol to first 40mg/day and then to 30mg/day due to skin toxicity.

Arm/Group Title	Afatinib 50 mg With Letrozole	Afatinib 40 mg With Letrozole	Afatinib 30 mg With Letrozole
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Period Title: Overall Study
STARTED	7	13	8
COMPLETED	0	0	0
NOT COMPLETED	7	13	8

Baseline Characteristics

Arm/Group Title	Afatinib 50 mg With Letrozole	Afatinib 40 mg With Letrozole	Afatinib 30 mg With Letrozole	Total
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Total of all reporting groups
Overall Participants	7	13	8	28
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.0 (14.7)	64.8 (7.2)	58.5 (9.0)	62.5 (10.0)
Sex: Female, Male (Count of Participants)
Female	7 100%	13 100%	8 100%	28 100%
Male	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Progression Free Participants After 16 Weeks of Treatment
Description	Progression was defined according to 1 of the following criteria: New bone lesion(s) on bone scan or on magnetic resonance imaging; Progression or occurrence of new lesion(s) according to the Response Evaluation Criteria In Solid Tumours version 1.0 (RECIST); an increase in tumour marker CA 15.3 of more than 20 percent,compared with baseline, at 2 consecutive examinations; occurrence of disease-related skeletal events. If a patient did not fulfil any criteria and was withdrawn because of clinical deterioration amounting to PD according to the Investigator, they were considered as having PD.
Time Frame	16 weeks

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 50 mg With Letrozole	Afatinib 40 mg With Letrozole	Afatinib 30 mg With Letrozole
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	7	13	8
Number (95% Confidence Interval) [Percentage of participants]	28.57 408.1%	0.00 0%	25.00 312.5%

2. Secondary Outcome

Title	Number of Participants With Confirmed Objective Response (OR)
Description	OR was defined as complete response (CR) or partial response (PR) and was assessed according to RECIST criteria regardless of treatment status.
Time Frame	Baseline till progression

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Afatinib 50 mg With Letrozole	Afatinib 40 mg With Letrozole	Afatinib 30 mg With Letrozole
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	7	13	8
Number [Participants]	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Number of Participants With Clinical Benefit (CB)
Description	CB was defined as CR, PR or stable disease (SD) and was assessed according to RECIST criteria regardless of treatment status.
Time Frame	16 weeks and 24 weeks

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Afatinib 50 mg With Letrozole	Afatinib 40 mg With Letrozole	Afatinib 30 mg With Letrozole
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	7	13	8
Participants with CB at 16 weeks	2 28.6%	2 15.4%	2 25%
Participants with CB at 24 weeks	2 28.6%	0 0%	2 25%

4. Secondary Outcome

Title	Time to RECIST Tumour Reponse
Description	The time to OR was the duration from the first treatment to the time when the measurement criteria for CR and/or PR were met according to RECIST criteria.
Time Frame	Baseline till progression

Outcome Measure Data

Analysis Population Description

TS. Median time to RECIST tumour response was not calculable as there was no OR observed.

Arm/Group Title	Afatinib 50 mg With Letrozole	Afatinib 40 mg With Letrozole	Afatinib 30 mg With Letrozole
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	7	13	8
Median (95% Confidence Interval) [days]	NA	NA	NA

5. Secondary Outcome

Title	Duration of Confirmed OR
Description	Duration of confirmed OR is measured from the time of first OR to the time of progression or death (or date of censoring for progression free survival).
Time Frame	First occurence or OR till progression or death

Outcome Measure Data

Analysis Population Description

TS. Median duration of RECIST tumour response was not calculable as there was no OR observed.

Arm/Group Title	Afatinib 50 mg With Letrozole	Afatinib 40 mg With Letrozole	Afatinib 30 mg With Letrozole
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	7	13	8
Median (95% Confidence Interval) [days]	NA	NA	NA

6. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was defined as the time from the first treatment to the occurrence of tumour progression or death, whichever came first. Progression was assessed according to RECIST criteria.
Time Frame	Baseline till progression, death or data cut-off (04 Jan 2010)

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Afatinib 50 mg With Letrozole	Afatinib 40 mg With Letrozole	Afatinib 30 mg With Letrozole
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	7	13	8
Median (95% Confidence Interval) [days]	60.0	107.0	79.0

7. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from first treatment to death.
Time Frame	Baseline till progression, death or data cut-off

Outcome Measure Data

Analysis Population Description

TS. Estimation of median time to death was not feasible, due to the small number of patients who died during the trial.

Arm/Group Title	Afatinib 50 mg With Letrozole	Afatinib 40 mg With Letrozole	Afatinib 30 mg With Letrozole
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	7	13	8
Median (95% Confidence Interval) [days]	NA	NA	NA

8. Secondary Outcome

Title	Area Under Curve of Afatinib Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss)
Description	AUCtau,ss represents the area under the concentration curve of afatinib in plasma over a uniform dosing interval tau at steady state.
Time Frame	0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Outcome Measure Data

Analysis Population Description

Data were particularly sparse for the 50 mg starting dose group and were not summarised.

Arm/Group Title	Afatinib 40 mg	Afatinib 30 mg
Arm/Group Description	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	4	5
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	660 (41.3)	579 (62.8)

9. Secondary Outcome

Title	Maximum Concentration of Afatinib in Plasma at Steady State (Cmax,ss)
Description	Cmax,ss represents the maximum measured concentration of afatinib in plasma at steady state.
Time Frame	0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Outcome Measure Data

Analysis Population Description

Data were particularly sparse for the 50 mg starting dose group and were not summarised.

Arm/Group Title	Afatinib 40 mg	Afatinib 30 mg
Arm/Group Description	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	4	5
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	43.8 (42.0)	33.9 (79.4)

10. Secondary Outcome

Title	Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 57 (Cpre,ss,57)
Description	Cpre,ss,57 represents the pre-dose concentration of afatinib in plasma at steady state on day 57.
Time Frame	Day 57

Outcome Measure Data

Analysis Population Description

Data were particularly sparse for the 50 mg starting dose group and were not summarised.

Arm/Group Title	Afatinib 40 mg	Afatinib 30 mg
Arm/Group Description	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	5	8
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	21.4 (42.3)	15.8 (42.1)

11. Secondary Outcome

Title	Pre-dose Concentration of Afatinib in Plasma at Steady Stateon Day 85 (Cpre,ss,85)
Description	Cpre,ss,85 represents the pre-dose concentration of afatinib in plasma at steady state on day 85.
Time Frame	Day 85

Outcome Measure Data

Analysis Population Description

Data were particularly sparse for the 50 mg starting dose group and were not summarised.

Arm/Group Title	Afatinib 40 mg	Afatinib 30 mg
Arm/Group Description	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	4	5
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	16.9 (55.7)	17.3 (46.5)

12. Secondary Outcome

Title	Time From Dosing to the Maximum Concentration of Afatinib in Plasma at Steady State (Tmax,ss)
Description	tmax,ss represents the time from dosing to the maximum concentration of afatinib in plasma at steady state
Time Frame	0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Outcome Measure Data

Analysis Population Description

Data were particularly sparse for the 50 mg starting dose group and were not summarised.

Arm/Group Title	Afatinib 40 mg	Afatinib 30 mg
Arm/Group Description	Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.	Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	4	5
Median (Full Range) [hours]	2.00 (2.00-4.00)	4.00 (0.917-7.67)

13. Secondary Outcome

Title	Area Under Curve of Letrozole Over a Uniform Dosing Interval Tau at Steady State (AUCtau,ss)
Description	AUC0-tau,ss represents the area under the concentration curve of letrozole in plasma over a uniform dosing interval tau at steady state.
Time Frame	0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Outcome Measure Data

Analysis Population Description

Analysis of all treatment arms combined, as Letrozole dose was the same in all arms.

Arm/Group Title	Afatinib Overall, With Letrozole 2.5 mg
Arm/Group Description	Patients received continuous daily dosing with Afatinib 30, 40 or 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	2420 (76.2)

14. Secondary Outcome

Title	Maximum Concentration of Letrozole in Plasma at Steady State (Cmax,ss)
Description	Cmax,ss represents the maximum measured concentration of letrozole in plasma at steady state.
Time Frame	0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Outcome Measure Data

Analysis Population Description

Analysis of all treatment arms combined, as Letrozole dose was the same in all arms.

Arm/Group Title	Afatinib Overall, With Letrozole 2.5mg
Arm/Group Description	Patients received continuous daily dosing with Afatinib 30, 40 or 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	10
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	135 (70.0)

15. Secondary Outcome

Title	Time From Dosing to the Maximum Concentration of Letrozole in Plasma at Steady State (Tmax,ss)
Description	tmax,ss represents the time from dosing to the maximum concentration of letrozole in plasma at steady state.
Time Frame	0.05 hours (h) before dosing and 2h, 4h, 6h, 8h and 24h after dosing

Outcome Measure Data

Analysis Population Description

Analysis of all treatment arms combined, as Letrozole dose was the same in all arms.

Arm/Group Title	Afatinib Overall, With Letrozole 2.5mg
Arm/Group Description	Patients received continuous daily dosing with Afatinib 30, 40 or 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	10
Median (Full Range) [hours]	1.00

16. Secondary Outcome

Title	Change From Baseline in Ca15.3
Description	Change from baseline in Ca15.3 tumor marker levels
Time Frame	baseline and day 29

Outcome Measure Data

Analysis Population Description

Analysis of all treatment arms combined for tumor marker analysis.

Arm/Group Title	Afatinib Overall
Arm/Group Description	Patients received continuous daily dosing with Afatinib 30, 40 or 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	21
Median (Full Range) [percentage of baseline level]	-4.35

17. Secondary Outcome

Title	Best Change From Baseline in ECOG Performance Status
Description	Best change from baseline in ECOG (Eastern Cooperative Oncology Group) performance status. ECOG is measured as score between 0 (fully active) and 5 (dead). Improvement is a decrease in ECOG score from baseline of at least 1. Deterioration is an increase in ECOG score from baseline of at least 1
Time Frame	baseline till end of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Afatinib Overall
Arm/Group Description	Patients received continuous daily dosing with Afatinib 30, 40 or 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
Measure Participants	28
Improved	4 57.1%
Deteriorated	6 85.7%
Unchanged	16 228.6%
Not done	2 28.6%

Adverse Events

Time Frame	First administration of trial medication until 28 days after last administration of trial medication
Arm/Group Title	Afatinib 50 mg With Letrozole		Afatinib 40 mg With Letrozole		Afatinib 30 mg With Letrozole
Arm/Group Description	Patients received continuous daily dosing with Afatinib 50 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.		Patients received continuous daily dosing with Afatinib 40 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.		Patients received continuous daily dosing with Afatinib 30 mg therapy with letrozole 2.5 mg over 28-day treatment cycles until further disease progression.
All Cause Mortality
	Afatinib 50 mg With Letrozole		Afatinib 40 mg With Letrozole		Afatinib 30 mg With Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Afatinib 50 mg With Letrozole		Afatinib 40 mg With Letrozole		Afatinib 30 mg With Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)		3/13 (23.1%)		5/8 (62.5%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Gastrointestinal disorders
Diarrhoea	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Nausea	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Vomiting	0/7 (0%)		1/13 (7.7%)		1/8 (12.5%)
General disorders
Asthenia	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Mucosal inflammation	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Obstruction	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Oedema peripheral	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Infections and infestations
Arthritis bacterial	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Erysipelas	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Pneumococcal sepsis	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Post precedural sepsis	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Sinusitis	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Metabolism and nutrition disorders
Dehydration	0/7 (0%)		1/13 (7.7%)		1/8 (12.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Pain in extremity	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Spinal disorder	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Melanocytic naevus	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Neoplasm progression	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Psychiatric disorders
Depression	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Mood altered	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Renal and urinary disorders
Renal failure acute	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Vascular disorders
Jugular vein thrombosis	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Afatinib 50 mg With Letrozole		Afatinib 40 mg With Letrozole		Afatinib 30 mg With Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		13/13 (100%)		8/8 (100%)
Blood and lymphatic system disorders
Anaemia	0/7 (0%)		1/13 (7.7%)		2/8 (25%)
Neutropenia	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Cardiac disorders
Cardiac failure	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Ear and labyrinth disorders
Tinnitus	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Vertigo	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Eye disorders
Conjunctivitis	2/7 (28.6%)		2/13 (15.4%)		2/8 (25%)
Dry eye	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Eye irritation	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Eye pain	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Eyelid disorder	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Eyelid irritation	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Photopsia	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Gastrointestinal disorders
Abdominal pain	3/7 (42.9%)		1/13 (7.7%)		2/8 (25%)
Abdominal pain upper	1/7 (14.3%)		1/13 (7.7%)		1/8 (12.5%)
Anorectal discomfort	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Aphthous stomatitis	1/7 (14.3%)		1/13 (7.7%)		2/8 (25%)
Cheilitis	1/7 (14.3%)		1/13 (7.7%)		0/8 (0%)
Diarrhoea	7/7 (100%)		12/13 (92.3%)		7/8 (87.5%)
Dry mouth	0/7 (0%)		2/13 (15.4%)		0/8 (0%)
Dyspepsia	2/7 (28.6%)		0/13 (0%)		0/8 (0%)
Dysphagia	0/7 (0%)		1/13 (7.7%)		1/8 (12.5%)
Gingival bleeding	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Gingival pain	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Haemorrhoids	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Lip dry	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Nausea	4/7 (57.1%)		4/13 (30.8%)		3/8 (37.5%)
Oesophagitis	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Oral pain	1/7 (14.3%)		0/13 (0%)		3/8 (37.5%)
Rectal haemorrhage	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Stomatitis	1/7 (14.3%)		3/13 (23.1%)		0/8 (0%)
Vomiting	2/7 (28.6%)		2/13 (15.4%)		0/8 (0%)
Constipation	3/7 (42.9%)		1/13 (7.7%)		3/8 (37.5%)
General disorders
Asthenia	4/7 (57.1%)		8/13 (61.5%)		4/8 (50%)
Catheter site inflammation	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Chest pain	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Cyst	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Facial pain	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Fatigue	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Hypothermia	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Inflammation	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Malaise	1/7 (14.3%)		0/13 (0%)		1/8 (12.5%)
Mucosal inflammation	5/7 (71.4%)		3/13 (23.1%)		2/8 (25%)
Oedema	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Oedema peripheral	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Pain	2/7 (28.6%)		0/13 (0%)		0/8 (0%)
Pyrexia	1/7 (14.3%)		0/13 (0%)		1/8 (12.5%)
Hepatobiliary disorders
Jaundice cholestatic	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Immune system disorders
Food allergy	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Infections and infestations
Cystitis	2/7 (28.6%)		0/13 (0%)		1/8 (12.5%)
Folliculitis	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Fungal infection	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Fungal skin infection	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Herpes simplex	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Herpes virus infection	0/7 (0%)		0/13 (0%)		2/8 (25%)
Hordeolum	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Influenza	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Laryngitis	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Localised infection	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Nail infection	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Nasopharyngitis	1/7 (14.3%)		1/13 (7.7%)		0/8 (0%)
Paronychia	1/7 (14.3%)		1/13 (7.7%)		2/8 (25%)
Rhinitis	1/7 (14.3%)		1/13 (7.7%)		0/8 (0%)
Urinary tract infection	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Vaginal infection	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Vulvovaginal mycotic infection	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Injury, poisoning and procedural complications
Fall	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Thermal burn	1/7 (14.3%)		0/13 (0%)		1/8 (12.5%)
Metabolism and nutrition disorders
Decreased appetite	1/7 (14.3%)		4/13 (30.8%)		2/8 (25%)
Hypokalaemia	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/7 (14.3%)		2/13 (15.4%)		1/8 (12.5%)
Back pain	2/7 (28.6%)		1/13 (7.7%)		1/8 (12.5%)
Bone pain	1/7 (14.3%)		0/13 (0%)		3/8 (37.5%)
Muscle spasm	2/7 (28.6%)		0/13 (0%)		1/8 (12.5%)
Musculoskeletal chest pain	0/7 (0%)		0/13 (0%)		2/8 (25%)
Musculoskeletal pain	1/7 (14.3%)		1/13 (7.7%)		1/8 (12.5%)
Myalgia	0/7 (0%)		2/13 (15.4%)		0/8 (0%)
Neck pain	2/7 (28.6%)		0/13 (0%)		0/8 (0%)
Osteoporosis	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Pain in extremity	2/7 (28.6%)		0/13 (0%)		3/8 (37.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Nervous system disorders
Dizziness	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Dysgeusia	0/7 (0%)		4/13 (30.8%)		2/8 (25%)
Epiduritis	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Headache	4/7 (57.1%)		0/13 (0%)		2/8 (25%)
Neuralgia	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Neuropathy peripheral	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Sciatica	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Psychiatric disorders
Anxiety	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Insomnia	0/7 (0%)		1/13 (7.7%)		1/8 (12.5%)
Renal and urinary disorders
Dysuria	0/7 (0%)		3/13 (23.1%)		0/8 (0%)
Pollakiuria	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Reproductive system and breast disorders
Breast pain	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Genital burning sensation	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Vulvovaginal discomfort	0/7 (0%)		1/13 (7.7%)		1/8 (12.5%)
Vulvovaginal dryness	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/7 (14.3%)		2/13 (15.4%)		3/8 (37.5%)
Dysphonia	2/7 (28.6%)		0/13 (0%)		0/8 (0%)
Dyspnoea	1/7 (14.3%)		1/13 (7.7%)		1/8 (12.5%)
Epistaxis	3/7 (42.9%)		5/13 (38.5%)		3/8 (37.5%)
Haemoptysis	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Nasal dryness	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Nasal mucosal disorder	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Nasal ulcer	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Oropharyngeal pain	1/7 (14.3%)		1/13 (7.7%)		0/8 (0%)
Pleural effusion	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Rhinorrhoea	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Skin and subcutaneous tissue disorders
Acne	5/7 (71.4%)		3/13 (23.1%)		1/8 (12.5%)
Alopecia	2/7 (28.6%)		0/13 (0%)		2/8 (25%)
Dermatitis acneiform	0/7 (0%)		5/13 (38.5%)		1/8 (12.5%)
Dry skin	3/7 (42.9%)		0/13 (0%)		1/8 (12.5%)
Erythema	0/7 (0%)		0/13 (0%)		2/8 (25%)
Exfoliative rash	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Hirsutism	1/7 (14.3%)		1/13 (7.7%)		0/8 (0%)
Nail disorder	4/7 (57.1%)		0/13 (0%)		1/8 (12.5%)
Palmar-plantar erythrodysaesthesia syndrome	2/7 (28.6%)		0/13 (0%)		0/8 (0%)
Pruritus	2/7 (28.6%)		0/13 (0%)		1/8 (12.5%)
Rash	5/7 (71.4%)		5/13 (38.5%)		6/8 (75%)
Skin fissures	2/7 (28.6%)		0/13 (0%)		1/8 (12.5%)
Skin irritation	0/7 (0%)		0/13 (0%)		1/8 (12.5%)
Skin toxicity	0/7 (0%)		1/13 (7.7%)		0/8 (0%)
Vascular disorders
Hot flush	1/7 (14.3%)		0/13 (0%)		0/8 (0%)
Pallor	0/7 (0%)		0/13 (0%)		1/8 (12.5%)

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.