Phase II Trial of BIBW 2992 (Afatinib) in Genetically Pre-screened Cancers With EGFR and/or HER2 Gene Amplification.

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00748709
• Collaborator: (none)
• Enrollment: 20
• Locations: 15
• Arm: 1
• Patients Per Site: 1.3

Study Details

Study Description

Brief Summary

This is a Phase II open-label exploratory trial of BIBW 2992 administered to patients with tumors of various histologies found to possess EGFR and/or HER2 gene amplification, or EGFR activating mutations.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms	Drug: BIBW 2992 (Afatinib)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Phase II Trial of BIBW 2992 (Afatinib) in Genetically Pre-screened Cancers With EGFR and/or HER2 Gene Amplification or EFGR Activating Mutations.
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BIBW 2992 (Afatinib) BIBW 2992 (Afatinib) for patients FISH positive for/or harboring EGFR or HER2 Mutation	Drug: BIBW 2992 (Afatinib); BIBW 2992 (Afatininb) for patients FISH positive for/or harboring EGFR or HER2 Mutation

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Objective Response (OR) [Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks thereafter]

   OR is defined as the percentage of patients with complete response (CR) or partial response (PR) and was assessed according to the Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST 1.0).

Secondary Outcome Measures

1. Percentage of Participants With Clinical Benefit (CB) [Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks till database lock]

   CB was defined as CR, PR or stable disease (SD) and was assessed according to RECIST 1.0 criteria.

2. Time to Objective Response (OR) [Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks till database lock]

   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 1.0 criteria.

3. Duration of OR [Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks till database lock.]

   Duration of OR was measured from the time the criteria for CR or PR (whichever was documented first) were first met until the first date that progressive disease or death was objectively documented.

4. Progression-free Survival (PFS) [Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks till database lock.]

   PFS was defined as the time from the start of treatment to the occurrence of disease progression or death, whichever came first. Disease progression was assessed according to RECIST 1.0 criteria as well as by the investigators assessment, progression date recorded from post trial follow up or start of new anticancer treatment.

5. Patients With AEs Resulting in Dose Reduction or Treatment Discontinuation [First administration of trial medication until 28 days after last administration of trial medication]

   Patients with adverse events (AEs) resulting in dose reduction or treatment discontinuation

6. Maximum CTCAE Grade [First administration of trial medication until 28 days after last administration of trial medication]

   Patients with AEs by maximum Common Terminology Criteria for Adverse Events (CTCAE) grade

7. Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 15 (Cpre,ss,15) for Patients on 50mg on Day 15 [Day 15]

   Cpre,ss,15 represents the pre-dose concentration of afatinib in plasma at steady state on day 15 for patients on 50mg on day 15.

8. Number of Patients With Diarrhea or Rash [First administration of trial medication until 28 days after last administration of trial medication]

   Number of Patients with Diarrhea or Rash

Eligibility Criteria

Criteria

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

Inclusion criteria:

There are 2 Steps in the screening process:

Step 1 Inclusion criteria for pre-screening:

1. Histologically confirmed diagnosis of advanced cancer of one of the following four tumor type categories:

Category 1, Gastric, GE junction, or Esophageal cancer Category 2, Biliary or gallbladder cancer Category 3, TCC urothelial tract, and Category 4, Gynecological cancers

1. Measurable disease by RECIST criteria.

2. Willingness and ability to give written informed consents consistent with ICHGCP guidelines.

3. Life expectancy of at least three (3) months.

4. Eastern Cooperative Oncology Group performance score 0, 1 or 2.

5. Age >18 years.

Step 2 Inclusion criteria for enrollment:

Patients who have tested positive for FISH and are considered candidate for this trial must meet all of the following inclusion criteria:

1. Histologically confirmed diagnosis of advanced cancer of one of the following four tumor type categories:

Category 1, Gastric, GE junction, or Esophageal cancer Category 2, Biliary or gallbladder cancer Category 3, TCC urothelial tract, and Category 4, Gynecological cancers

1. Documented failure to respond or progression of underlying cancer after at least one line of prior chemotherapy.

2. EGFR and/or HER2 gene amplification by FISH testing or patients with tumors that harbor known activating EGFR mutations.

3. Measurable disease by RECIST criteria.

4. Willingness and ability to give written informed consents consistent with ICH-GCP guidelines.

5. Life expectancy of at least three (3) months.

6. Eastern Cooperative Oncology Group performance score 0, 1 or 2.

7. Age >18 years.

Exclusion criteria:

1. Prior treatment with gefitinib, erlotinib, lapatinib and/or other EGFR TKIs.

2. Treatment with cytotoxic anti-cancer-therapies or investigational drugs during the last four weeks prior to the first treatment with the trial drug. (a shorter duration may be considered for patients treated with oral, non cytotoxic drugs on an individual basis and upon discussion between the principal investigator and sponsor)

3. Inability to take BIBW 2992 by mouth (BIBW 2992 may not be crushed or administered via Gastrostomy-tube)

4. Chronic diarrhea or other gastrointestinal disorders that may interfere with the absorption of the trial drug.

5. History of other malignancies unless free of disease for at least 3 years (except for appropriately treated superficial non-melanoma skin cancer and surgically cured cervical cancer in situ).

6. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to randomization.

7. Resting left ventricular ejection fraction <50% OR below the institution's lower limit of normal (if the institutions lower limit is above 50%), measured by MUGA scan or echocardiogram.

8. Active infectious disease

9. Serious illness, concomitant non-oncological disease or mental problems considered by the investigator to be incompatible with participation in this trial.

10. Active/symptomatic brain metastases. Patients with a history of treated brain metastases must have stable or normal brain MRI scan at screening and be at least three months post-radiation or surgery for brain metastasis.

11. Absolute Neutrophil Count (ANC) less than 1,000/mm3.

12. Platelet count less than 100,000/mm3.

13. Hemoglobin Level less than 9.0 grams/dl.

14. Total Bilirubin greater than 1.5 mg/dl; higher Total Bilirubin values may be acceptable for patients with known Gilbert¿s disease, approval by the PI and sponsor will be necessary.

15. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 times the upper limit of normal; or 5 times the upper limit of normal in patients with neoplastic liver involvement.

16. Serum creatinine greater than 1.5 x upper limit of normal for the institution.

17. Patients who are sexually active and unwilling to use simultaneously two medically acceptable method of contraception, one of which being a barrier type method such as condom.

18. Pregnancy or breast-feeding.

19. Patients unable to comply with the protocol

20. Active alcohol and/or substance abuse.

21. Continuation of therapy-related toxicities from prior anti cancer therapies, prior surgery, of CTCAE Grade >=2 at the time of the first administration of the trial drug.

22. Patients with known pre-existing interstitial lung disease.

23. Requirement for treatment with any of the prohibited concomitant medications: additional experimental anti-cancer treatment and/or standard chemotherapy, immunotherapy, hormone treatment or radiotherapy; P-gp inhibitors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1200.26.3 Boehringer Ingelheim Investigational Site	Los Angeles	California	United States
2	1200.26.11 Boehringer Ingelheim Investigational Site	Denver	Colorado	United States
3	1200.26.9 Boehringer Ingelheim Investigational Site	Indianapolis	Indiana	United States
4	1200.26.1 Boehringer Ingelheim Investigational Site	Boston	Massachusetts	United States
5	1200.26.13 Boehringer Ingelheim Investigational Site	Las Vegas	Nevada	United States
6	1200.26.4 Boehringer Ingelheim Investigational Site	Albany	New York	United States
7	1200.26.2 Boehringer Ingelheim Investigational Site	New York	New York	United States
8	1200.26.7 Boehringer Ingelheim Investigational Site	Kettering	Ohio	United States
9	1200.26.12 Boehringer Ingelheim Investigational Site	Dallas	Texas	United States
10	1200.26.8 Boehringer Ingelheim Investigational Site	Tyler	Texas	United States
11	1200.26.6 Boehringer Ingelheim Investigational Site	Norfolk	Virginia	United States
12	1200.26.10 Boehringer Ingelheim Investigational Site	Vancouver	Washington	United States
13	1200.26.88603 Boehringer Ingelheim Investigational Site	Tainan		Taiwan
14	1200.26.88601 Boehringer Ingelheim Investigational Site	Taipei		Taiwan
15	1200.26.88602 Boehringer Ingelheim Investigational Site	Tao-Yuan		Taiwan

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
• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00748709
• Other Study ID Numbers: 1200.26
• First Posted: Sep 9, 2008
• Last Update Posted: Nov 28, 2013
• Last Verified: Nov 1, 2013

• Additional relevant MeSH terms: Afatinib

Study Results

Participant Flow

Recruitment Details	"The trial was terminated earlier than planned because of a high screen-failure rate and recruitment challenges that prevented full accrual; no safety or efficacy findings influenced this decision. "

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Period Title: Overall Study
STARTED	20
COMPLETED	0
NOT COMPLETED	20

Baseline Characteristics

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Overall Participants	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.1 (6.2)
Sex: Female, Male (Count of Participants)
Female	6 30%
Male	14 70%

Outcome Measures

1. Secondary Outcome

Title	Percentage of Participants With Clinical Benefit (CB)
Description	CB was defined as CR, PR or stable disease (SD) and was assessed according to RECIST 1.0 criteria.
Time Frame	Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks till database lock

Outcome Measure Data

Analysis Population Description

TS.

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Measure Participants	20
With CB	45.0
Without CB	55.0

2. Secondary Outcome

Title	Time to Objective Response (OR)
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 1.0 criteria.
Time Frame	Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks till database lock

Outcome Measure Data

Analysis Population Description

Trial terminated early, therefore no data summaries produced for time to OR.

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Measure Participants	0

3. Secondary Outcome

Title	Duration of OR
Description	Duration of OR was measured from the time the criteria for CR or PR (whichever was documented first) were first met until the first date that progressive disease or death was objectively documented.
Time Frame	Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks till database lock.

Outcome Measure Data

Analysis Population Description

Trial terminated early, therefore no data summaries produced for duration of OR.

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Measure Participants	0

4. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was defined as the time from the start of treatment to the occurrence of disease progression or death, whichever came first. Disease progression was assessed according to RECIST 1.0 criteria as well as by the investigators assessment, progression date recorded from post trial follow up or start of new anticancer treatment.
Time Frame	Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks till database lock.

Outcome Measure Data

Analysis Population Description

Trial terminated early, therefore no data summaries produced for PFS.

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Measure Participants	0

5. Secondary Outcome

Title	Patients With AEs Resulting in Dose Reduction or Treatment Discontinuation
Description	Patients with adverse events (AEs) resulting in dose reduction or treatment discontinuation
Time Frame	First administration of trial medication until 28 days after last administration of trial medication

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Measure Participants	20
With AE leading to drug discontinuation	5 25%
With AE leading to dose reduction	1 5%
With Treatment held or paused due to AE	8 40%

6. Secondary Outcome

Title	Maximum CTCAE Grade
Description	Patients with AEs by maximum Common Terminology Criteria for Adverse Events (CTCAE) grade
Time Frame	First administration of trial medication until 28 days after last administration of trial medication

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Measure Participants	20
Grade 1	2 10%
Grade 2	5 25%
Grade 3	10 50%
Grade 4	0 0%
Grade 5	3 15%

7. Primary Outcome

Title	Percentage of Participants With Objective Response (OR)
Description	OR is defined as the percentage of patients with complete response (CR) or partial response (PR) and was assessed according to the Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST 1.0).
Time Frame	Tumour assessments were performed at screening, week 6, week 12, and every 8 weeks thereafter

Outcome Measure Data

Analysis Population Description

Treated Set (TS). TS consisted of all patients who received at least one dose of trial medication.

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Measure Participants	20
Number [percentage of patients]	5.0

8. Secondary Outcome

Title	Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 15 (Cpre,ss,15) for Patients on 50mg on Day 15
Description	Cpre,ss,15 represents the pre-dose concentration of afatinib in plasma at steady state on day 15 for patients on 50mg on day 15.
Time Frame	Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Measure Participants	12
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	33.2 (80.0)

9. Secondary Outcome

Title	Number of Patients With Diarrhea or Rash
Description	Number of Patients with Diarrhea or Rash
Time Frame	First administration of trial medication until 28 days after last administration of trial medication

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
Measure Participants	20
AE : Diarrhea	18 90%
AE : Rash	12 60%

Adverse Events

Time Frame	First administration of trial medication until 28 days after last administration of trial medication
Arm/Group Title	Afatinib 50mg
Arm/Group Description	Patients with genetically pre-screened cancers with EGFR and/or HER2 gene amplification or EGFR activating mutations treated with afatinib 50mg once daily.
All Cause Mortality
	Afatinib 50mg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Afatinib 50mg
	Affected / at Risk (%)	# Events
Total	6/20 (30%)
Gastrointestinal disorders
Diarrhoea	1/20 (5%)
Infections and infestations
Escherichia bacteraemia	1/20 (5%)
Metabolism and nutrition disorders
Dehydration	1/20 (5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	2/20 (10%)
Reproductive system and breast disorders
Female genital tract fistula	1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/20 (10%)
Pleural effusion	1/20 (5%)
Other (Not Including Serious) Adverse Events
	Afatinib 50mg
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
Anaemia	4/20 (20%)
Gastrointestinal disorders
Constipation	3/20 (15%)
Diarrhoea	17/20 (85%)
Dyspepsia	2/20 (10%)
Nausea	7/20 (35%)
Stomatitis	4/20 (20%)
Vomiting	7/20 (35%)
General disorders
Chest pain	2/20 (10%)
Fatigue	9/20 (45%)
Oedema peripheral	2/20 (10%)
Infections and infestations
Paronychia	6/20 (30%)
Urinary tract infection	4/20 (20%)
Investigations
Blood creatinine increased	2/20 (10%)
Weight decreased	4/20 (20%)
Metabolism and nutrition disorders
Decreased appetite	11/20 (55%)
Dehydration	4/20 (20%)
Hypokalaemia	2/20 (10%)
Hypomagnesaemia	3/20 (15%)
Musculoskeletal and connective tissue disorders
Back pain	2/20 (10%)
Muscle spasms	2/20 (10%)
Musculoskeletal pain	2/20 (10%)
Nervous system disorders
Dizziness	2/20 (10%)
Dysgeusia	3/20 (15%)
Psychiatric disorders
Insomnia	4/20 (20%)
Renal and urinary disorders
Haematuria	2/20 (10%)
Respiratory, thoracic and mediastinal disorders
Cough	2/20 (10%)
Epistaxis	4/20 (20%)
Rhinorrhoea	2/20 (10%)
Skin and subcutaneous tissue disorders
Alopecia	2/20 (10%)
Dermatitis acneiform	6/20 (30%)
Dry skin	4/20 (20%)
Pruritus	4/20 (20%)
Rash	12/20 (60%)
Vascular disorders
Hypotension	2/20 (10%)

Limitations/Caveats

Due to early study termination, only data on the primary efficacy endpoint were summarized, no CIs were produced and efficacy and safety results were presented for the overall population rather than by tumor category.

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