Afatinib (BIBW 2992) in Advanced Non-Small Cell Lung Cancer Patients With EGFR Mutation

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01953913
• Collaborator: (none)
• Enrollment: 542
• Locations: 33
• Arm: 1
• Actual Duration (Months): 57.2
• Patients Per Site: 16.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Primary objective of the trial is to evaluate the safety of afatinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR (Epidermal growth factor receptor) mutation(s) and have never been treated with an EGFR-TKI (tyrosine kinase inhibitor). Secondary objective is to assess the time to symptomatic progression (as judged by investigator).

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Afatinib	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 542 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label, Multicentre, Single Arm Trial to Assess the Safety of Afatinib for Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) Harboring EGFR Mutation(s)
• Actual Study Start Date: Sep 30, 2013
• Actual Primary Completion Date: Jul 6, 2018
• Actual Study Completion Date: Jul 6, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Afatinib Patient will receive afatinib once daily	Drug: Afatinib; Patient will receive afatinib once daily

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Serious Adverse Events (SAEs) [From first drug administration up to 28 days after last drug administration, up to 1624 days.]

   Percentage of participants with serious adverse events (SAEs).

Secondary Outcome Measures

1. Time to Symptomatic Progression (TTSP) [From first drug administration until date of first documented clinically significant symptomatic progression that required stopping afatinib treatment, up to 1624 days.]

   Time to Symptomatic progression (TTSP) was defined as time from first administration of afatinib to date of first documented clinically significant symptomatic progression that required stopping the anti-cancer treatment according to investigator's assessment. 95% confidence intervals (CIs) for the median was calculated for TTSP using Greenwood' standard error estimate.

2. Percentage of Participants With Drug-related (Afatinib-related) Adverse Events [From first drug administration up to 28 days after last drug administration, up to 1624 days.]

   Percentage of participants with drug-related (afatinib-related) adverse events.

Eligibility Criteria

Criteria

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

Inclusion criteria:

• locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC)

• presence of Epidermal Growth Factor Receptor (EGFR) mutations in tumor biopsy

• male or female patients age 18 years or older (For India only, male or female patients age >=18 years and <=75 years)

• adequate organ function, defined as all of the following:

1. Absolute Neutrophil Count (ANC) > 1500/mm3. (ANC >1000/mm3 may be considered in special circumstances such as benign cyclical neutropenia as judged by the investigator and in discussion with the sponsor).

2. Platelet count >75,000/mm3

3. Serum creatinine < 1.5 times of the upper limit of normal

4. Total Bilirubin < 1.5 times upper limit of (institutional) normal (Patients with Gilbert's syndrome total bilirubin must be <4 times institutional upper limit of normal).

5. Aspartate Amino Transferase (AST) and Alanine Amino Transferase (ALT) < three times the upper limit of (institutional) normal (ULN) (if related to liver metastases < five times ULN). 5) Eastern Cooperative Oncology Group (ECOG) score between 0 - 2 6) written informed consent by patient or guardian prior to admission into the trial that is consistent with International Conference on Harmonisation (ICH)- Good Clinical Practice (GCP) guidelines and local law.

Exclusion criteria:

• prior treatment with an EGFR tyrosine kinase inhibitor (TKI)

• use of anti-cancer treatment within 2 weeks prior to start of trial treatment (continued use of anti-androgens and / or gonadorelin analogues for treatment of prostate cancer permitted)

• radiotherapy within 4 weeks prior to drug administration except as follows:

1. palliative radiation to organs other than chest may be allowed up to 2 weeks prior to drug administration, and

2. single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor prior to enrolling.

• major surgery within 4 weeks from day 1 of first dose of afatinib. At least 7 days should have elapsed since minor surgical procedure including placement of an access device or fine needle aspiration and at least 14 days for diagnostic or palliative video-assisted thoracoscopic surgery (VATS).

• known hypersensitivity to afatinib or any of its excipients

• history or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of >3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to starting trial treatment.

• Women of Child-Bearing Potential (WOCBP) and men who are able to father a child, unwilling to be abstinent or use medically acceptable method of contraception during the trial entry and for at least 4 weeks after treatment has ended. Adequate methods of contraception and Women of Child-Bearing Potential. Perimenopausal women must be amenorrhoeic for at least 24 months to be considered for non-childbearing potential.

• childbearing potential (see Section 4.2.3) who:

1. are nursing or

2. are pregnant or

3. are not using an acceptable method of birth control, or do not plan to continue using this method throughout the trial and/or do not agree to submit to pregnancy testing required by this protocol

• history of or co-existing condition that, in the opinion of the investigator, would compromise the patient's ability to comply with the trial or interfere with the evaluation of safety for the trial drug

• previous or concomitant malignancies at other sites, except effectively treated nonmelanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured.

• requiring treatment with any of the prohibited concomitant medications listed, that cannot be stopped for the duration of trial participation

• known pre-existing interstitial lung disease

• presence of poorly controlled gastrointestinal disorders that could affect the absorption of the trial drug (e.g. Crohn's disease, ulcerative colitis, malabsorption, or CTC grade =2 diarrhoea of any aetiology) based on investigator assessment.

• Known active hepatitis B infection (defined as presence of Hepatitis B (HepB) sAg and/or HepB DNA), active Hepatitis C (HEP C) infection (defined as presence of Hep C RNA) and/or known Human Immunodeficiency Virus (HIV) carrier.

• meningeal carcinomatosis

• symptomatic brain metastases (patients with brain metastases, who were previously treated, are eligible provided they have asymptomatic brain metastasis for at least 4 weeks on stable doses of medication)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	307 Hospital of PLA	Beijing		China	100071
2	Beijing Cancer Hospital	Beijing		China	100142
3	Chinese PLA General Hospital	Beijing		China	100853
4	Jilin Province Cancer Hospital	Changchun		China
5	Guangdong Provincial People's Hospital	Guangzhou		China	510080
6	Zhejiang Cancer Hospital	Hangzhou		China	310022
7	Lin Yi Tumor Hospital	Linyi		China	276002
8	Jiangsu Cancer Hospital	Nanjing		China	210000
9	Shanghai Chest Hospital	Shanghai		China	200030
10	Fudan University Shanghai Cancer Center	Shanghai		China	200032
11	Shanghai Pulmonary Hospital	Shanghai		China	200433
12	Tianjin Medical University Cancer Institute and Hospital	Tianjin		China	300060
13	Queen Mary Hospital	Hong Kong		Hong Kong
14	Prince of Wales Hospital	Shatin		Hong Kong
15	Vikram Hospital	Bangalore		India	560052
16	HCG Hospital	Bengaluru		India	560027
17	P VS Hospital Pvt Ltd	Calicut		India	673002
18	V S Hospital	Chennai		India	600031
19	Max Super Speciality Hospital, Delhi	Delhi		India	110092
20	Global Hospitals	Hyderabad		India	500004
21	Basavatarakam Indo - American Cancer Hospital & Research Ins	Hyderabad		India	500034
22	SEAROC Cancer Centre	Jaipur		India	302004
23	B. P. Poddar Hospital & Medial Research Ltd	Kolkata,West Bengal		India	700053
24	Asirvatham Multispeciality Hospital	Madurai		India	625 020
25	Curie Manavata Cancer Centre	Maharashtra		India	422 004
26	Shatabdi Superspeciality Hospital	Maharashtra		India	422005
27	Prince Aly Khan Hospital	Mumbai		India	400010
28	Ruby Hall Clinic	Pune		India	411001
29	National Cancer Centre	Singapore		Singapore	169610
30	E-Da Hospital	Kaohsiung		Taiwan	824
31	NCKUH	Tainan		Taiwan	704
32	Tri-Service General Hospital	Taipei		Taiwan	11490
33	Chang-Gung Memorial Hospital, Linkou	Taoyuan County		Taiwan	333

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 28, 2017
• Study Protocol - Feb 3, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01953913
• Other Study ID Numbers: 1200.66
• First Posted: Oct 1, 2013
• Last Update Posted: Aug 12, 2019
• Last Verified: Jun 1, 2019

• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Afatinib

Study Results

Participant Flow

Recruitment Details	Participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation(s), who have never been treated with an EGFR-tyrosine kinase inhibitor (TKI) were recruited in the phase IIIb open label, multicentre, single-arm trial.
Pre-assignment Detail	All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that they (all participants) met all inclusion/exclusion criteria. Participants were not to be entered to trial treatment if any one of the specific entry criteria were not met.

Arm/Group Title	Afatinib
Arm/Group Description	Participants received Afatinib 40 milligram (mg)/30 mg/20 mg film-coated tablets orally with 250 milliliter (mL) of water, once daily of every 28-day treatment cycle.
Period Title: Overall Study
STARTED	542
Treated	541
COMPLETED	0
NOT COMPLETED	542

Baseline Characteristics

Arm/Group Title	Afatinib
Arm/Group Description	Participants received Afatinib 40 milligram (mg)/30 mg/20 mg film-coated tablets orally with 250 milliliter (mL) of water, once daily of every 28-day treatment cycle.
Overall Participants	541
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.3 (9.7)
Sex: Female, Male (Count of Participants)
Female	286 52.9%
Male	255 47.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 0.7%
Not Hispanic or Latino	537 99.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	541 100%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Serious Adverse Events (SAEs)
Description	Percentage of participants with serious adverse events (SAEs).
Time Frame	From first drug administration up to 28 days after last drug administration, up to 1624 days.

Outcome Measure Data

Analysis Population Description

Treated set (TS): It included all patients who were dispensed trial medication and documented to take at least one dose of investigational treatment (afatinib).

Arm/Group Title	Afatinib
Arm/Group Description	Participants received Afatinib 40 milligram (mg)/30 mg/20 mg film-coated tablets orally with 250 milliliter (mL) of water, once daily of every 28-day treatment cycle.
Measure Participants	541
Number [Percentage of participants (%)]	30.3 5.6%

2. Secondary Outcome

Title	Time to Symptomatic Progression (TTSP)
Description	Time to Symptomatic progression (TTSP) was defined as time from first administration of afatinib to date of first documented clinically significant symptomatic progression that required stopping the anti-cancer treatment according to investigator's assessment. 95% confidence intervals (CIs) for the median was calculated for TTSP using Greenwood' standard error estimate.
Time Frame	From first drug administration until date of first documented clinically significant symptomatic progression that required stopping afatinib treatment, up to 1624 days.

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Afatinib
Arm/Group Description	Participants received Afatinib 40 milligram (mg)/30 mg/20 mg film-coated tablets orally with 250 milliliter (mL) of water, once daily of every 28-day treatment cycle.
Measure Participants	541
Median (95% Confidence Interval) [Months]	13.99

3. Secondary Outcome

Title	Percentage of Participants With Drug-related (Afatinib-related) Adverse Events
Description	Percentage of participants with drug-related (afatinib-related) adverse events.
Time Frame	From first drug administration up to 28 days after last drug administration, up to 1624 days.

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Afatinib
Arm/Group Description	Participants received Afatinib 40 milligram (mg)/30 mg/20 mg film-coated tablets orally with 250 milliliter (mL) of water, once daily of every 28-day treatment cycle.
Measure Participants	541
Number [Percentage of participants (%)]	97.6 18%

Adverse Events

Time Frame	For adverse events: From first drug administration up to 28 days after last drug administration, up to 1624 days. For All-cause Mortality: From first drug administration to database lock date, up to 1771 days.
Adverse Event Reporting Description	TS. As per the clinical trial protocol, survival follow-up was not required and was not done routinely.
Arm/Group Title	Afatinib
Arm/Group Description	Participants received Afatinib 40 milligram (mg)/30 mg/20 mg film-coated tablets orally with 250 milliliter (mL) of water, once daily of every 28- day treatment cycle.
All Cause Mortality
	Afatinib
	Affected / at Risk (%)	# Events
Total	46/541 (8.5%)
Serious Adverse Events
	Afatinib
	Affected / at Risk (%)	# Events
Total	164/541 (30.3%)
Blood and lymphatic system disorders
Anaemia	2/541 (0.4%)
Hypochromic anaemia	1/541 (0.2%)
Cardiac disorders
Acute myocardial infarction	1/541 (0.2%)
Cardiac arrest	2/541 (0.4%)
Cardiac tamponade	2/541 (0.4%)
Cardiogenic shock	1/541 (0.2%)
Cardiomyopathy	1/541 (0.2%)
Myocarditis	1/541 (0.2%)
Pericardial effusion	2/541 (0.4%)
Eye disorders
Cataract	1/541 (0.2%)
Gastrointestinal disorders
Abdominal discomfort	1/541 (0.2%)
Anal haemorrhage	1/541 (0.2%)
Ascites	1/541 (0.2%)
Diarrhoea	10/541 (1.8%)
Duodenal obstruction	1/541 (0.2%)
Gastritis	1/541 (0.2%)
Gastrointestinal disorder	1/541 (0.2%)
Gastrointestinal haemorrhage	1/541 (0.2%)
Gastrooesophageal reflux disease	1/541 (0.2%)
Ileus	2/541 (0.4%)
Intestinal obstruction	2/541 (0.4%)
Mallory-Weiss syndrome	1/541 (0.2%)
Nausea	1/541 (0.2%)
Odynophagia	1/541 (0.2%)
Pancreatitis	2/541 (0.4%)
Proctitis	1/541 (0.2%)
Stomatitis	3/541 (0.6%)
Vomiting	5/541 (0.9%)
Vomiting projectile	1/541 (0.2%)
General disorders
Chest pain	1/541 (0.2%)
Death	3/541 (0.6%)
General physical health deterioration	1/541 (0.2%)
Mucosal inflammation	1/541 (0.2%)
Non-cardiac chest pain	1/541 (0.2%)
Oedema peripheral	1/541 (0.2%)
Pain	1/541 (0.2%)
Peripheral swelling	1/541 (0.2%)
Pyrexia	3/541 (0.6%)
Hepatobiliary disorders
Cholecystitis	1/541 (0.2%)
Hepatic lesion	1/541 (0.2%)
Infections and infestations
Bronchitis	2/541 (0.4%)
Cellulitis	1/541 (0.2%)
Device related infection	1/541 (0.2%)
Empyema	1/541 (0.2%)
Escherichia sepsis	1/541 (0.2%)
Gastroenteritis	1/541 (0.2%)
Lower respiratory tract infection	1/541 (0.2%)
Lung infection	3/541 (0.6%)
Nasopharyngitis	1/541 (0.2%)
Osteomyelitis	1/541 (0.2%)
Pneumonia	7/541 (1.3%)
Pseudomonal sepsis	1/541 (0.2%)
Sepsis	1/541 (0.2%)
Septic shock	1/541 (0.2%)
Tuberculosis	1/541 (0.2%)
Upper respiratory tract infection	2/541 (0.4%)
Urinary tract infection	4/541 (0.7%)
Urosepsis	1/541 (0.2%)
Viral infection	1/541 (0.2%)
Injury, poisoning and procedural complications
Fall	2/541 (0.4%)
Muscle strain	1/541 (0.2%)
Investigations
Alanine aminotransferase increased	2/541 (0.4%)
Aspartate aminotransferase increased	1/541 (0.2%)
Blood bilirubin increased	1/541 (0.2%)
Blood creatinine increased	2/541 (0.4%)
Urine output decreased	1/541 (0.2%)
Weight decreased	1/541 (0.2%)
Metabolism and nutrition disorders
Decreased appetite	3/541 (0.6%)
Hyperuricaemia	2/541 (0.4%)
Hypokalaemia	4/541 (0.7%)
Musculoskeletal and connective tissue disorders
Back pain	3/541 (0.6%)
Bone pain	2/541 (0.4%)
Muscular weakness	1/541 (0.2%)
Musculoskeletal pain	1/541 (0.2%)
Myalgia	1/541 (0.2%)
Pain in extremity	2/541 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma	1/541 (0.2%)
Cancer pain	1/541 (0.2%)
Lung neoplasm malignant	1/541 (0.2%)
Malignant neoplasm progression	18/541 (3.3%)
Metastases to bone	1/541 (0.2%)
Metastases to central nervous system	8/541 (1.5%)
Metastases to lung	1/541 (0.2%)
Metastases to meninges	5/541 (0.9%)
Metastases to spine	1/541 (0.2%)
Neoplasm malignant	1/541 (0.2%)
Neoplasm progression	1/541 (0.2%)
Soft tissue neoplasm	1/541 (0.2%)
Nervous system disorders
Altered state of consciousness	1/541 (0.2%)
Cerebral infarction	5/541 (0.9%)
Cerebral ischaemia	1/541 (0.2%)
Cognitive disorder	2/541 (0.4%)
Coma	1/541 (0.2%)
Dementia Alzheimer's type	1/541 (0.2%)
Dizziness	3/541 (0.6%)
Epilepsy	2/541 (0.4%)
Headache	2/541 (0.4%)
Hemiparesis	1/541 (0.2%)
Hydrocephalus	1/541 (0.2%)
Lethargy	1/541 (0.2%)
Loss of consciousness	1/541 (0.2%)
Movement disorder	1/541 (0.2%)
Paraplegia	1/541 (0.2%)
Seizure	2/541 (0.4%)
Speech disorder	1/541 (0.2%)
Spinal cord compression	1/541 (0.2%)
Syncope	1/541 (0.2%)
Psychiatric disorders
Confusional state	1/541 (0.2%)
Renal and urinary disorders
Acute kidney injury	2/541 (0.4%)
Hydronephrosis	1/541 (0.2%)
Renal impairment	2/541 (0.4%)
Ureterolithiasis	1/541 (0.2%)
Reproductive system and breast disorders
Bartholin's cyst	1/541 (0.2%)
Benign prostatic hyperplasia	1/541 (0.2%)
Respiratory, thoracic and mediastinal disorders
Cough	1/541 (0.2%)
Dyspnoea	15/541 (2.8%)
Haemoptysis	2/541 (0.4%)
Interstitial lung disease	2/541 (0.4%)
Pleural effusion	16/541 (3%)
Pneumonitis	1/541 (0.2%)
Pneumothorax	5/541 (0.9%)
Pulmonary embolism	1/541 (0.2%)
Pulmonary haemorrhage	1/541 (0.2%)
Pulmonary hypertension	1/541 (0.2%)
Pulmonary oedema	1/541 (0.2%)
Respiratory failure	6/541 (1.1%)
Skin and subcutaneous tissue disorders
Rash	1/541 (0.2%)
Skin ulcer	1/541 (0.2%)
Vascular disorders
Deep vein thrombosis	3/541 (0.6%)
Hypotension	1/541 (0.2%)
Hypovolaemic shock	1/541 (0.2%)
Superior vena cava stenosis	1/541 (0.2%)
Other (Not Including Serious) Adverse Events
	Afatinib
	Affected / at Risk (%)	# Events
Total	529/541 (97.8%)
Blood and lymphatic system disorders
Anaemia	48/541 (8.9%)
Gastrointestinal disorders
Diarrhoea	483/541 (89.3%)
Mouth ulceration	145/541 (26.8%)
Nausea	43/541 (7.9%)
Stomatitis	135/541 (25%)
Vomiting	54/541 (10%)
General disorders
Asthenia	38/541 (7%)
Chest pain	33/541 (6.1%)
Fatigue	29/541 (5.4%)
Mucosal inflammation	57/541 (10.5%)
Pyrexia	43/541 (7.9%)
Infections and infestations
Paronychia	271/541 (50.1%)
Rhinitis	37/541 (6.8%)
Upper respiratory tract infection	58/541 (10.7%)
Urinary tract infection	33/541 (6.1%)
Investigations
Alanine aminotransferase increased	77/541 (14.2%)
Aspartate aminotransferase increased	67/541 (12.4%)
Gamma-glutamyltransferase increased	36/541 (6.7%)
Weight decreased	70/541 (12.9%)
Metabolism and nutrition disorders
Decreased appetite	81/541 (15%)
Hypocalcaemia	38/541 (7%)
Hypokalaemia	53/541 (9.8%)
Musculoskeletal and connective tissue disorders
Back pain	48/541 (8.9%)
Nervous system disorders
Dizziness	38/541 (7%)
Headache	33/541 (6.1%)
Respiratory, thoracic and mediastinal disorders
Cough	132/541 (24.4%)
Dyspnoea	52/541 (9.6%)
Epistaxis	37/541 (6.8%)
Haemoptysis	32/541 (5.9%)
Nasal dryness	32/541 (5.9%)
Oropharyngeal pain	28/541 (5.2%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	29/541 (5.4%)
Dry skin	47/541 (8.7%)
Palmar-plantar erythrodysaesthesia syndrome	41/541 (7.6%)
Pruritus	52/541 (9.6%)
Rash	383/541 (70.8%)

Limitations/Caveats

[Not Specified]

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.