Phase I Trial of Afatinib and Trastuzumab in HER2 Overexpressing Cancer.

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01649271
• Collaborator: (none)
• Enrollment: 13
• Locations: 3
• Arms: 3
• Actual Duration (Months): 47
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The aim of the study is to determine the Maximum Tolerated Dose (MTD) of afatinib in combination with 3-weekly trastuzumab in HER2 overexpressing cancer and to assess the efficacy of afatinib given at the MTD dosage, with 3-weekly trastuzumab in HER2 overexpressing metastatic breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms; Stomach Neoplasms	Drug: Herceptin; Drug: afatinib; Drug: trastuzumab; Drug: Herceptin; Drug: afatinib; Drug: afatinib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Trial of Afatinib in Combination With 3 Weekly Trastuzumab in Patients With Tumours Overexpressing HER2. Once the MTD of Afatinib With 3 Weekly Trastuzumab Was Established the Safety of This Dose Will be Assessed Also in Combination With Weekly Trastuzumab.
• Actual Study Start Date: Jul 23, 2012
• Actual Primary Completion Date: Jun 23, 2016
• Actual Study Completion Date: Jun 23, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase Ia, group 1 afatinib escalating dose with 3-weekly trastuzumab	Drug: Herceptin; 3-weekly; Drug: afatinib; escalating dose
Experimental: Phase Ia, group 2 afatinib at MTD dose with weekly trastuzumab	Drug: afatinib; at MTD level; Drug: Herceptin; weekly
Experimental: Phase Ib afatinib at MTD level with 3-weekly trastuzumab	Drug: trastuzumab; 3-weekly; Drug: afatinib; at MTD level

Outcome Measures

Primary Outcome Measures

1. MTD of Afatinib in Combination With Trastuzumab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib). [First 21 days treatment cycle]

   Maximum Tolerated Dose (MTD) of Afatinib in combination with trastuzumab based on the number of patients with dose limiting toxicity (DLT) during the first treatment cycle (Dose escalation part). The MTD was defined as the highest dose studied at which the incidence of a DLT was less than 17% (i.e. 1/6 patients) during the first cycle. One patient in the Afa30+Trast8 cohort developed tumour lysis syndrome during the first course of treatment and was therefore not evaluable for the primary endpoint.

2. Dose Limiting Toxicities During cycle1 [First 21-day treatment cycle]

   Number of Patients With Dose Limiting Toxicity (DLT) occurring during Cycle 1 based on the investigator assessment. One patient in the Afa30+Trast8 cohort developed tumour lysis syndrome during the first course of treatment and was therefore not evaluable for the primary endpoint.

Secondary Outcome Measures

1. Best Overall Response (BOR) [Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until End of Treatment (EOT); up to 33 months]

   BOR represents the best response a patient had during their time in study from start of treatment until progression, the last evaluable assessment in absence of progression or start of subsequent anticancer therapy. For patients that died, BOR was to be calculated based on data up to last evaluable RECIST,v1.1 assessment prior to death. Death did not contribute as PD for BOR. As per RECIST v1.1 for target lesions (TL) & assessed by MRI: CR: Disappearance of all TL,all non-TL, & no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least 30% decrease in sum of the longest diameter (SLD) of TL taking as reference the baseline SLD. PD: At least a 20% increase in SLD of TL taking as reference the smallest SLD recorded since treatment started, together with an absolute increase in SLD of at least 5mm. SD: Neither sufficient shrinkage to qualify for PR, taking as reference the baseline SLD, nor sufficient increase to qualify for PD.

2. Objective Response [Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 33 months]

   Objective Response (OR) was defined as best overall response of complete response (CR) or partial response (PR), where best overall response was determined according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 from first administration of study medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy. As Per RECIST v1.1 for target lesions (TL) & assessed by MRI: CR: Disappearance of all TL,all non-TL, & no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least 30% decrease in sum of the longest diameter (SLD) of TL taking as reference the baseline SLD.

3. Clinical Benefit [Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 33 months]

   Clinical benefit was defined as best overall response of CR or PR or stable disease (SD) where best overall response is defined according to RECIST version 1.1 from first treatment administration until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy. As Per RECIST v1.1 for target lesions (TL) & assessed by MRI: CR: Disappearance of all TL,all non-TL, & no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least 30% decrease in sum of the longest diameter (SLD) of TL taking as reference the baseline SLD. SD: Neither sufficient shrinkage to qualify for PR, taking as reference the baseline SLD, nor sufficient increase to qualify for PD.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Patients aged 18 years and older

2. Patients with cancers overexpressing HER2 by Immunohistochemistry test( IHC) 3+ and/or IHC 2+ with positive gene amplification by FISH (confirmation on archived tissue needed)

3. Written informed consent that is consistent with ICH-GCP guidelines.

4. Patients must be eligible for treatment with trastuzumab.

5. Patients must have adequate organ function (kidney, liver, bone marrow, cardiac)

6. Eastern Cooperative Oncology Group (ECOG) = 0 or 1.

7. Measurable disease according to RECIST 1.1 (Phase Ib).

Exclusion criteria:

1. Active brain metastases.

2. Prior treatment with erbB family targeting therapies within the past four weeks before start of therapy or concomitantly with the trial other than trastuzumab and/or lapatinib.

3. Patients having more than 2 lines of chemotherapy for the treatment of metastatic breast cancer (Phase Ib).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CTR Georges-François Leclerc	Dijon		France	21079
2	CTR René Gauducheau, Onco, St Herblain	Saint Herblain Cedex		France	44805
3	INS Claudius Regaud	Toulouse		France	31059

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01649271
• Other Study ID Numbers: 1200.134; 2012-001753-10
• First Posted: Jul 25, 2012
• Last Update Posted: Dec 22, 2017
• Last Verified: Nov 1, 2017

• Additional relevant MeSH terms: Neoplasms; Breast Neoplasms; Stomach Neoplasms; Trastuzumab; Afatinib

Study Results

Participant Flow

Recruitment Details	HER2: Human Epidermal Growth Factor Receptor 2; RECIST,v1.1: Response Evaluation Criteria In Solid Tumors, version 1.1
Pre-assignment Detail	Phase Ia: Open label, uncontrolled, dose escalation study of afatinib given continuously in combination with trastuzumab administered every 3 weeks. Phase Ib: Open label, uncontrolled study to explore the efficacy, safety, pharmacokinetics & biomarkers of afatinib at the MTD dosage, with 3- weekly trastuzumab.

Arm/Group Title	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg	Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg
Arm/Group Description	In each 21 day treatment cycle, patients were administered orally 20 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.	In each 21 day treatment cycle, patients were administered orally 30 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.
Period Title: Overall Study
STARTED	6	7
COMPLETED	0	0
NOT COMPLETED	6	7

Baseline Characteristics

Arm/Group Title	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg	Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg	Total
Arm/Group Description	In each 21 day treatment cycle, patients were administered orally 20 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.	In each 21 day treatment cycle, patients were administered orally 30 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.	Total of all reporting groups
Overall Participants	6	7	13
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.8 (3.7)	48.4 (7.6)	54.2 (8.7)
Sex: Female, Male (Count of Participants)
Female	4 66.7%	7 100%	11 84.6%
Male	2 33.3%	0 0%	2 15.4%

Outcome Measures

1. Primary Outcome

Title	MTD of Afatinib in Combination With Trastuzumab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib).
Description	Maximum Tolerated Dose (MTD) of Afatinib in combination with trastuzumab based on the number of patients with dose limiting toxicity (DLT) during the first treatment cycle (Dose escalation part). The MTD was defined as the highest dose studied at which the incidence of a DLT was less than 17% (i.e. 1/6 patients) during the first cycle. One patient in the Afa30+Trast8 cohort developed tumour lysis syndrome during the first course of treatment and was therefore not evaluable for the primary endpoint.
Time Frame	First 21 days treatment cycle

Outcome Measure Data

Analysis Population Description

Treated set: This analysis set includes all patients who were documented to have taken at least one dose of study medication.

Arm/Group Title	Phase Ia: Afatinib +Trastuzumab 8 mg/kg
Arm/Group Description	In each 21 day treatment cycle, patients were administered orally afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.
Measure Participants	12
Number [mg]	20

2. Primary Outcome

Title	Dose Limiting Toxicities During cycle1
Description	Number of Patients With Dose Limiting Toxicity (DLT) occurring during Cycle 1 based on the investigator assessment. One patient in the Afa30+Trast8 cohort developed tumour lysis syndrome during the first course of treatment and was therefore not evaluable for the primary endpoint.
Time Frame	First 21-day treatment cycle

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg	Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg
Arm/Group Description	In each 21 day treatment cycle, patients were administered orally 20 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.	In each 21 day treatment cycle, patients were administered orally 30 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.
Measure Participants	6	6
Count of Participants [Participants]	1 16.7%	2 28.6%

3. Secondary Outcome

Title	Best Overall Response (BOR)
Description	BOR represents the best response a patient had during their time in study from start of treatment until progression, the last evaluable assessment in absence of progression or start of subsequent anticancer therapy. For patients that died, BOR was to be calculated based on data up to last evaluable RECIST,v1.1 assessment prior to death. Death did not contribute as PD for BOR. As per RECIST v1.1 for target lesions (TL) & assessed by MRI: CR: Disappearance of all TL,all non-TL, & no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least 30% decrease in sum of the longest diameter (SLD) of TL taking as reference the baseline SLD. PD: At least a 20% increase in SLD of TL taking as reference the smallest SLD recorded since treatment started, together with an absolute increase in SLD of at least 5mm. SD: Neither sufficient shrinkage to qualify for PR, taking as reference the baseline SLD, nor sufficient increase to qualify for PD.
Time Frame	Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until End of Treatment (EOT); up to 33 months

Outcome Measure Data

Analysis Population Description

Treated set Missing: First image time point not reached before discontinuation.

Arm/Group Title	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg	Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg
Arm/Group Description	In each 21 day treatment cycle, patients were administered orally 20 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.	In each 21 day treatment cycle, patients were administered orally 30 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.
Measure Participants	6	7
Complete Response (CR)	0.0 0%	0.0 0%
Partial Response (PR)	16.7 278.3%	0.0 0%
Stable Disease (SD)	16.7 278.3%	100.0 1428.6%
Progressive Disease (PD)	50.0 833.3%	0.0 0%
Missing	16.7 278.3%	0.0 0%
Not Evaluable	0.0 0%	0.0 0%

4. Secondary Outcome

Title	Objective Response
Description	Objective Response (OR) was defined as best overall response of complete response (CR) or partial response (PR), where best overall response was determined according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 from first administration of study medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy. As Per RECIST v1.1 for target lesions (TL) & assessed by MRI: CR: Disappearance of all TL,all non-TL, & no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least 30% decrease in sum of the longest diameter (SLD) of TL taking as reference the baseline SLD.
Time Frame	Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 33 months

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg	Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg
Arm/Group Description	In each 21 day treatment cycle, patients were administered orally 20 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.	In each 21 day treatment cycle, patients were administered orally 30 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.
Measure Participants	6	7
Number [percentage of participants]	16.7 278.3%	0.0 0%

5. Secondary Outcome

Title	Clinical Benefit
Description	Clinical benefit was defined as best overall response of CR or PR or stable disease (SD) where best overall response is defined according to RECIST version 1.1 from first treatment administration until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy. As Per RECIST v1.1 for target lesions (TL) & assessed by MRI: CR: Disappearance of all TL,all non-TL, & no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least 30% decrease in sum of the longest diameter (SLD) of TL taking as reference the baseline SLD. SD: Neither sufficient shrinkage to qualify for PR, taking as reference the baseline SLD, nor sufficient increase to qualify for PD.
Time Frame	Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 33 months

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg	Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg
Arm/Group Description	In each 21 day treatment cycle, patients were administered orally 20 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.	In each 21 day treatment cycle, patients were administered orally 30 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.
Measure Participants	6	7
Number [percentage of participants]	33.3 555%	100.0 1428.6%

Adverse Events

Time Frame	From first dose administration of the study medication to 28 days after last drug administration; up to 33 months
Arm/Group Title	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg		Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg
Arm/Group Description	In each 21 day treatment cycle, patients were administered orally 20 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.		In each 21 day treatment cycle, patients were administered orally 30 mg afatinib tablet from Day 2 continuous daily administration in combination with trastuzumab. An initial loading dose of trastuzumab 8 mg/kg was administered via intravenous infusion at Day1 Cycle1, followed by trastuzumab 6 mg/kg every 3 weeks. Trastuzumab intravenous infusion, 90 minutes, infusion duration could be reduced to 30 minutes if well tolerated.
All Cause Mortality
	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg		Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg		Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		4/7 (57.1%)
Gastrointestinal disorders
Diarrhoea	1/6 (16.7%)		1/7 (14.3%)
General disorders
Chest pain	1/6 (16.7%)		0/7 (0%)
General physical health deterioration	0/6 (0%)		1/7 (14.3%)
Hepatobiliary disorders
Biliary colic	1/6 (16.7%)		0/7 (0%)
Infections and infestations
Clostridium difficile colitis	0/6 (0%)		1/7 (14.3%)
Injury, poisoning and procedural complications
Infusion related reaction	1/6 (16.7%)		0/7 (0%)
Metabolism and nutrition disorders
Hypokalaemia	0/6 (0%)		1/7 (14.3%)
Tumour lysis syndrome	0/6 (0%)		1/7 (14.3%)
Nervous system disorders
Spinal cord compression	0/6 (0%)		1/7 (14.3%)
Renal and urinary disorders
Acute kidney injury	0/6 (0%)		1/7 (14.3%)
Renal failure	0/6 (0%)		1/7 (14.3%)
Vascular disorders
Jugular vein thrombosis	0/6 (0%)		1/7 (14.3%)
Other (Not Including Serious) Adverse Events
	Phase Ia: Afatinib 20mg+Trastuzumab 8 mg/kg		Phase Ia: Afatinib 30mg+Trastuzumab 8 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Anaemia	0/6 (0%)		1/7 (14.3%)
Cardiac disorders
Cardiotoxicity	0/6 (0%)		1/7 (14.3%)
Eye disorders
Dry eye	1/6 (16.7%)		0/7 (0%)
Lacrimation increased	1/6 (16.7%)		0/7 (0%)
Visual acuity reduced	0/6 (0%)		1/7 (14.3%)
Gastrointestinal disorders
Abdominal distension	0/6 (0%)		1/7 (14.3%)
Abdominal pain	0/6 (0%)		1/7 (14.3%)
Abdominal pain upper	0/6 (0%)		1/7 (14.3%)
Cheilitis	0/6 (0%)		1/7 (14.3%)
Constipation	0/6 (0%)		2/7 (28.6%)
Diarrhoea	6/6 (100%)		6/7 (85.7%)
Duodenal ulcer	1/6 (16.7%)		0/7 (0%)
Gastrooesophageal reflux disease	0/6 (0%)		1/7 (14.3%)
Mouth ulceration	1/6 (16.7%)		0/7 (0%)
Nausea	2/6 (33.3%)		1/7 (14.3%)
Perianal erythema	0/6 (0%)		1/7 (14.3%)
Stomatitis	0/6 (0%)		3/7 (42.9%)
Tongue oedema	0/6 (0%)		1/7 (14.3%)
Vomiting	0/6 (0%)		1/7 (14.3%)
General disorders
Asthenia	4/6 (66.7%)		5/7 (71.4%)
Face oedema	0/6 (0%)		1/7 (14.3%)
Fatigue	0/6 (0%)		1/7 (14.3%)
Influenza like illness	0/6 (0%)		1/7 (14.3%)
Pyrexia	0/6 (0%)		1/7 (14.3%)
Xerosis	0/6 (0%)		1/7 (14.3%)
Hepatobiliary disorders
Cholestasis	0/6 (0%)		1/7 (14.3%)
Gallbladder obstruction	1/6 (16.7%)		0/7 (0%)
Hepatocellular injury	1/6 (16.7%)		1/7 (14.3%)
Infections and infestations
Bronchitis	0/6 (0%)		2/7 (28.6%)
Conjunctivitis	1/6 (16.7%)		0/7 (0%)
Cystitis	0/6 (0%)		1/7 (14.3%)
Folliculitis	0/6 (0%)		1/7 (14.3%)
Herpes virus infection	0/6 (0%)		1/7 (14.3%)
Herpes zoster	1/6 (16.7%)		0/7 (0%)
Nasopharyngitis	1/6 (16.7%)		0/7 (0%)
Oral herpes	1/6 (16.7%)		1/7 (14.3%)
Paronychia	1/6 (16.7%)		5/7 (71.4%)
Rash pustular	1/6 (16.7%)		0/7 (0%)
Urinary tract infection	0/6 (0%)		1/7 (14.3%)
Investigations
Alanine aminotransferase increased	1/6 (16.7%)		0/7 (0%)
Aspartate aminotransferase increased	1/6 (16.7%)		0/7 (0%)
Blood bilirubin increased	0/6 (0%)		1/7 (14.3%)
Blood creatinine increased	1/6 (16.7%)		1/7 (14.3%)
Ejection fraction decreased	0/6 (0%)		2/7 (28.6%)
Glomerular filtration rate decreased	0/6 (0%)		1/7 (14.3%)
Weight decreased	0/6 (0%)		2/7 (28.6%)
Metabolism and nutrition disorders
Decreased appetite	1/6 (16.7%)		3/7 (42.9%)
Hyperuricaemia	1/6 (16.7%)		0/7 (0%)
Hypokalaemia	1/6 (16.7%)		2/7 (28.6%)
Hypomagnesaemia	1/6 (16.7%)		1/7 (14.3%)
Hyponatraemia	0/6 (0%)		1/7 (14.3%)
Vitamin D deficiency	0/6 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)		0/7 (0%)
Back pain	0/6 (0%)		1/7 (14.3%)
Muscle spasms	3/6 (50%)		0/7 (0%)
Pain in extremity	1/6 (16.7%)		1/7 (14.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pyogenic granuloma	1/6 (16.7%)		0/7 (0%)
Nervous system disorders
Headache	0/6 (0%)		1/7 (14.3%)
Paraesthesia	1/6 (16.7%)		0/7 (0%)
Psychiatric disorders
Depression	0/6 (0%)		1/7 (14.3%)
Renal and urinary disorders
Renal failure	0/6 (0%)		1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/6 (16.7%)		1/7 (14.3%)
Nasal dryness	2/6 (33.3%)		0/7 (0%)
Nasal mucosal disorder	1/6 (16.7%)		0/7 (0%)
Rhinorrhoea	1/6 (16.7%)		1/7 (14.3%)
Skin and subcutaneous tissue disorders
Acne	1/6 (16.7%)		0/7 (0%)
Dermatitis acneiform	1/6 (16.7%)		1/7 (14.3%)
Dry skin	1/6 (16.7%)		1/7 (14.3%)
Eczema	0/6 (0%)		1/7 (14.3%)
Erythema	1/6 (16.7%)		1/7 (14.3%)
Nail disorder	1/6 (16.7%)		1/7 (14.3%)
Onycholysis	1/6 (16.7%)		0/7 (0%)
Pruritus	0/6 (0%)		1/7 (14.3%)
Rash	2/6 (33.3%)		5/7 (71.4%)
Skin exfoliation	0/6 (0%)		1/7 (14.3%)
Skin fissures	1/6 (16.7%)		1/7 (14.3%)
Skin reaction	0/6 (0%)		1/7 (14.3%)

Limitations/Caveats

Phase Ib was not started due to the discontinuation of afatinib development in HER2 overexpressing metastatic breast cancer and also the availability of other approved efficacious treatment options.Thus the results are not provided for Phase Ib.

More Information

Certain Agreements

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

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