Afatinib in NSCLC With HER2 Mutation

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02597946
• Collaborator: (none)
• Enrollment: 18
• Locations: 9
• Arm: 1
• Actual Duration (Months): 28.1
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

to investigate effectiveness and safety of afatinib in the advanced NSCLC patients with HER2 mutations, previously treated with 1 or 2 chemotherapy regimens

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: afatinib; Drug: paclitaxel	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Afatinib in Patients With Advanced NSCLC Harboring HER2 Mutations, Previously Treated With Chemotherapy
• Actual Study Start Date: Mar 18, 2016
• Actual Primary Completion Date: Jul 22, 2018
• Actual Study Completion Date: Jul 22, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: all patients Part A: all enrolled patients will receive afatinib monotherapy. Part B: all eligible patients will receive afatinib combined with weekly paclitaxel.	Drug: afatinib; Drug: paclitaxel

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients With Objective Response (OR) in Part A According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 [CT Scan at Weeks 8 & 12 (for week 12 tumor assessment, time window is +1week), then every 8 weeks thereafter, after week 52, assessments will be performed every 12 weeks until progression or start of further treatment , ie., up to approximately 12 Months]

   Percentage of patients with objective response (OR) in part A according to RECIST 1.1. Objective Response defined as patients with tumour size reduction of a predefined amount using RECIST 1.1 in part A. Objective response included both confirmed Partial Response (PR) plus Complete Response (CR) as measured by Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) according to RECIST 1.1. Partial Response (PR): At least a 30% decrease in the sum of longest diameter (LD) of target lesions asking as reference the baseline sum LD. Complete Response (CR): Disappearance of all target lesions.

Secondary Outcome Measures

1. Percentage of Patients With Disease Control (DC) in Part A [CT Scan at Weeks 8 & 12(for week 12 tumor assessment, time window is +1week), then every 8 weeks thereafter, after week 52, assessments will be performed every 12 weeks until progression or start of further treatment, ie up to approximately 12 Months]

   Percentage of patients with disease control (DC) in part A. Disease control defined as patients who have achieved confirmed complete response, partial response and stable disease as measured by CT scan or MRI according to RECIST 1.1 in part A. Tumour Response is based on clinical, radiological or other assessment. Clopper-Pearson method used for confidence limits. Partial Response (PR): At least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD. Complete Response (CR): Disappearance of all target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, taking as reference the baseline sum LD, nor sufficient increase to qualify for Progression (PD) taking as reference the smallest sum LD since the treatment started.

2. Progression Free Survival (PFS) in Part A [From the date of starting treatment of afatinib to the date of disease progression or to the date of death, ie up to approximately 12 Months]

   Progression Free Survival (PFS) defined as the time from the date of starting treatment of afatinib to the date of disease progression per RECIST 1.1, or to the date of death no matter which happens first in part A. Median and 95% confidence interval (CI) are calculated from an unadjusted Kaplan-Meier curve.

3. Overall Survival (OS) [From start of treatment of afatinib until death from any cause, ie up to approximately 12 Months]

   Overall survival (OS) defined as the time from start of treatment of afatinib until death from any cause. Median and 95% CI are calculated from an unadjusted Kaplan-Meier curve.

4. Time to Progression (TTP) in Part A [From the date of starting treatment of afatinib to the date of disease progression , ie up to approximately 12 Months]

   Time to progression (TTP) defined as the time from the date of starting treatment of afatinib to the date of disease progression per RECIST 1.1 in part A. Median and 95% CI are calculated from an unadjusted Kaplan-Meier curve.

5. Duration of Response (DOR) in Part A [CT Scan at Weeks 8 & 12(for week 12 tumor assessment, time window is +1week), then every 8 weeks thereafter, after week 52, assessments will be performed every 12 weeks until progression or start of further treatment, ie up to approximately 12 Months]

   Duration of response (DoR) defined as the time from the first documented response PR or CR to the date of tumor progression evaluated according to RECIST 1.1 or death in part A. Partial Response (PR): At least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD. Complete Response (CR): Disappearance of all target lesions. No patient had objective response and DoR was not analysed.

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Patients with Histologically or cytologically confirmed diagnosis of stage IIIb/IV NSCLC (AJCC 7.0), who had failed one or two systemic chemotherapy regimens, one of which must be platinum-based .

• Tumor tissue with HER2 mutations as confirmed by AmoyDx® HER2 Mutation Detection Kit

• Patients with at least one measurable tumor lesion that can accurately be measured by CT scan or MRI according to RECIST 1.1

• Age>=18 years

• Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1

• Adequate organ function

• Recovered from any previous therapy related toxicity to <=Grade 1 at study entry (except for stable sensory neuropathy <=Grade 2 and alopecia)

• Written informed consents that is consistent with International Conference on Harmonisation (ICH) - Good Clinical Practice (GCP) and local GCP guidelines Inclusion criterion for Part B

• Adequate organ function, as inclusion criteria No.6

• ECOG performance score 0~2

• More than 12 weeks clinical benefit (PR, Complete Response (CR), SD) in part A Further inclusion criteria apply

Exclusion criteria:

• Prior treatment with Epidermal Growth Factor Receptor (EGFR) or HER2 targeting small molecules or antibodies.

• Any chemo-, or immune anticancer therapy within 4 weeks prior to start of study treatment, Hormonal treatment within 2 weeks prior to start of study treatment,

Radiotherapy within 4 weeks prior to start of treatment, except as follows:

i.) Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to enter, and ii.) Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor prior to enrolling.

• Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study

• Known hypersensitivity to afatinib or the excipients of any of the trial drugs

• 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 randomisation.

• Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient's ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug.

• Previous or concomitant malignancies at other sites, except effectively treated non-melanoma 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

• Known pre-existing interstitial lung disease.

• Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug.

• Active hepatitis B infection and/or active hepatitis C infection and/or known HIV carrier.

• Leptomeningeal carcinomatosis.

• Symptomatic brain metastases; To be eligible patients must be asymptomatic from brain metastases at least 4 weeks without requirement for steroids or anti-epileptic therapy.

• Women of child-bearing potential (WOCBP) and men who are able to father a child, unwilling to be abstinent or use highly effective methods of birth control for the duration of study participation and for at least 2 weeks after treatment has ended.

• Women who are pregnant, nursing, or who plan to become pregnant while in the trial Exclusion criterion for Part B Any known contraindication for paclitaxel treatment. Not able to tolerate lowest dose of afatinib. Peripheral polyneuropathy >Grade 2 Further exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hunan Province Tumor Hospital	Changsha		China	410013
2	First Affiliated Hospital of Guangzhou Medical University	Guangzhou		China	510120
3	Zhejiang Cancer Hospital	Hangzhou		China	310022
4	The Second Affiliated Hospital to Nanchang University	Nanchang		China	330006
5	First Hospital Affiliated with Nanjing Medical University	Nanjing		China	210029
6	Zhongshan Hospital Fudan University	Shanghai		China	200032
7	Shanghai Pulmonary Hospital	Shanghai		China	200433
8	Henan Cancer Hospital	Zhengzhou		China	450008
9	University Malaya Medical Centre	Kuala Lumpur		Malaysia	59100

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Statistical Analysis Plan - Apr 16, 2018
• Study Protocol - Aug 16, 2017

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02597946
• Other Study ID Numbers: 1200.222
• First Posted: Nov 5, 2015
• Last Update Posted: Oct 1, 2019
• Last Verified: Sep 1, 2019

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

Study Results

Participant Flow

Recruitment Details	Open label, single arm study, divided into 2 parts; Part A: All enrolled patients will receive afatinib monotherapy.Part B: Patients with more than 12 weeks clinical benefit in part A will receive afatinib once daily combined with paclitaxel once weekly.
Pre-assignment Detail	No patients met the criteria to enter part B. Thus part B was not performed in this trial.

Arm/Group Title	Afatinib 40 mg (Part A)
Arm/Group Description	Patients were orally administered 40 milligram (mg) Afatinib film-coated tablets daily starting dose, once daily continuous (possible escalation to 50 mg, and reduction to 30 mg in the first step, and to 20 mg in the second step) until disease progression or intolerable toxicity or withdrawal of consent for any reason.
Period Title: Overall Study
STARTED	18
COMPLETED	0
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Afatinib 40 mg (Part A)
Arm/Group Description	Patients were orally administered 40 milligram (mg) Afatinib film-coated tablets daily starting dose, once daily continuous (possible escalation to 50 mg, and reduction to 30 mg in the first step, and to 20 mg in the second step) until disease progression or intolerable toxicity or withdrawal of consent for any reason.
Overall Participants	18
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.6 (7.6)
Sex: Female, Male (Count of Participants)
Female	12 66.7%
Male	6 33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	18 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	18 100%
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 Patients With Objective Response (OR) in Part A According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1
Description	Percentage of patients with objective response (OR) in part A according to RECIST 1.1. Objective Response defined as patients with tumour size reduction of a predefined amount using RECIST 1.1 in part A. Objective response included both confirmed Partial Response (PR) plus Complete Response (CR) as measured by Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) according to RECIST 1.1. Partial Response (PR): At least a 30% decrease in the sum of longest diameter (LD) of target lesions asking as reference the baseline sum LD. Complete Response (CR): Disappearance of all target lesions.
Time Frame	CT Scan at Weeks 8 & 12 (for week 12 tumor assessment, time window is +1week), then every 8 weeks thereafter, after week 52, assessments will be performed every 12 weeks until progression or start of further treatment , ie., up to approximately 12 Months

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Afatinib 40 mg (Part A)
Arm/Group Description	Patients were orally administered 40 milligram (mg) Afatinib film-coated tablets daily starting dose, once daily continuous (possible escalation to 50 mg, and reduction to 30 mg in the first step, and to 20 mg in the second step) until disease progression or intolerable toxicity or withdrawal of consent for any reason.
Measure Participants	18
Number [Percentage of participants]	0.0 0%

2. Secondary Outcome

Title	Percentage of Patients With Disease Control (DC) in Part A
Description	Percentage of patients with disease control (DC) in part A. Disease control defined as patients who have achieved confirmed complete response, partial response and stable disease as measured by CT scan or MRI according to RECIST 1.1 in part A. Tumour Response is based on clinical, radiological or other assessment. Clopper-Pearson method used for confidence limits. Partial Response (PR): At least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD. Complete Response (CR): Disappearance of all target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, taking as reference the baseline sum LD, nor sufficient increase to qualify for Progression (PD) taking as reference the smallest sum LD since the treatment started.
Time Frame	CT Scan at Weeks 8 & 12(for week 12 tumor assessment, time window is +1week), then every 8 weeks thereafter, after week 52, assessments will be performed every 12 weeks until progression or start of further treatment, ie up to approximately 12 Months

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Afatinib 40 mg (Part A)
Arm/Group Description	Patients were orally administered 40 milligram (mg) Afatinib film-coated tablets daily starting dose, once daily continuous (possible escalation to 50 mg, and reduction to 30 mg in the first step, and to 20 mg in the second step) until disease progression or intolerable toxicity or withdrawal of consent for any reason.
Measure Participants	18
Number (95% Confidence Interval) [Percentage of participants]	61.1 339.4%

3. Secondary Outcome

Title	Progression Free Survival (PFS) in Part A
Description	Progression Free Survival (PFS) defined as the time from the date of starting treatment of afatinib to the date of disease progression per RECIST 1.1, or to the date of death no matter which happens first in part A. Median and 95% confidence interval (CI) are calculated from an unadjusted Kaplan-Meier curve.
Time Frame	From the date of starting treatment of afatinib to the date of disease progression or to the date of death, ie up to approximately 12 Months

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Afatinib 40 mg (Part A)
Arm/Group Description	Patients were orally administered 40 milligram (mg) Afatinib film-coated tablets daily starting dose, once daily continuous (possible escalation to 50 mg, and reduction to 30 mg in the first step, and to 20 mg in the second step) until disease progression or intolerable toxicity or withdrawal of consent for any reason.
Measure Participants	18
Median (95% Confidence Interval) [Months]	2.76

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) defined as the time from start of treatment of afatinib until death from any cause. Median and 95% CI are calculated from an unadjusted Kaplan-Meier curve.
Time Frame	From start of treatment of afatinib until death from any cause, ie up to approximately 12 Months

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Afatinib 40 mg (Part A)
Arm/Group Description	Patients were orally administered 40 milligram (mg) Afatinib film-coated tablets daily starting dose, once daily continuous (possible escalation to 50 mg, and reduction to 30 mg in the first step, and to 20 mg in the second step) until disease progression or intolerable toxicity or withdrawal of consent for any reason.
Measure Participants	18
Median (95% Confidence Interval) [Months]	10.02

5. Secondary Outcome

Title	Time to Progression (TTP) in Part A
Description	Time to progression (TTP) defined as the time from the date of starting treatment of afatinib to the date of disease progression per RECIST 1.1 in part A. Median and 95% CI are calculated from an unadjusted Kaplan-Meier curve.
Time Frame	From the date of starting treatment of afatinib to the date of disease progression , ie up to approximately 12 Months

Outcome Measure Data

Analysis Population Description

Treated Set

Arm/Group Title	Afatinib 40 mg (Part A)
Arm/Group Description	Patients were orally administered 40 milligram (mg) Afatinib film-coated tablets daily starting dose, once daily continuous (possible escalation to 50 mg, and reduction to 30 mg in the first step, and to 20 mg in the second step) until disease progression or intolerable toxicity or withdrawal of consent for any reason.
Measure Participants	18
Median (95% Confidence Interval) [Months]	2.76

6. Secondary Outcome

Title	Duration of Response (DOR) in Part A
Description	Duration of response (DoR) defined as the time from the first documented response PR or CR to the date of tumor progression evaluated according to RECIST 1.1 or death in part A. Partial Response (PR): At least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD. Complete Response (CR): Disappearance of all target lesions. No patient had objective response and DoR was not analysed.
Time Frame	CT Scan at Weeks 8 & 12(for week 12 tumor assessment, time window is +1week), then every 8 weeks thereafter, after week 52, assessments will be performed every 12 weeks until progression or start of further treatment, ie up to approximately 12 Months

Outcome Measure Data

Analysis Population Description

No patient had objective response and DoR was not analysed.

Arm/Group Title	Afatinib 40 mg (Part A)
Arm/Group Description	Patients were orally administered 40 milligram (mg) Afatinib film-coated tablets daily starting dose, once daily continuous (possible escalation to 50 mg, and reduction to 30 mg in the first step, and to 20 mg in the second step) until disease progression or intolerable toxicity or withdrawal of consent for any reason.
Measure Participants	0

Adverse Events

Time Frame	From first drug administration until 30 days after the last dose, ie up to 272 days.
Arm/Group Title	Afatinib 40 mg (Part A)
Arm/Group Description	Patients were orally administered 40 milligram (mg) Afatinib film-coated tablets daily starting dose, once daily continuous (possible escalation to 50 mg, and reduction to 30 mg in the first step, and to 20 mg in the second step) until disease progression or intolerable toxicity or withdrawal of consent for any reason.
All Cause Mortality
	Afatinib 40 mg (Part A)
	Affected / at Risk (%)	# Events
Total	8/18 (44.4%)
Serious Adverse Events
	Afatinib 40 mg (Part A)
	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)
General disorders
Malaise	1/18 (5.6%)
Infections and infestations
Gastroenteritis	1/18 (5.6%)
Metabolism and nutrition disorders
Decreased appetite	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	2/18 (11.1%)
Pleural effusion	1/18 (5.6%)
Vascular disorders
Thrombosis	1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	Afatinib 40 mg (Part A)
	Affected / at Risk (%)	# Events
Total	18/18 (100%)
Blood and lymphatic system disorders
Anaemia	4/18 (22.2%)
Thrombocytopenia	1/18 (5.6%)
Gastrointestinal disorders
Abdominal pain	3/18 (16.7%)
Mouth ulceration	3/18 (16.7%)
Stomatitis	2/18 (11.1%)
Constipation	1/18 (5.6%)
Gingival swelling	1/18 (5.6%)
Nausea	1/18 (5.6%)
Tongue ulceration	1/18 (5.6%)
Vomiting	1/18 (5.6%)
Diarrhoea	12/18 (66.7%)
General disorders
Influenza like illness	1/18 (5.6%)
Pyrexia	1/18 (5.6%)
Infections and infestations
Upper respiratory tract infection	3/18 (16.7%)
Paronychia	2/18 (11.1%)
Lung infection	1/18 (5.6%)
Myringitis	1/18 (5.6%)
Pharyngitis	1/18 (5.6%)
Urinary tract infection	1/18 (5.6%)
Investigations
Aspartate aminotransferase increased	4/18 (22.2%)
Alanine aminotransferase increased	3/18 (16.7%)
Weight decreased	3/18 (16.7%)
Blood creatinine increased	1/18 (5.6%)
Blood glucose increased	1/18 (5.6%)
Blood urea increased	1/18 (5.6%)
Gamma-glutamyltransferase increased	1/18 (5.6%)
White blood cell count decreased	1/18 (5.6%)
Metabolism and nutrition disorders
Decreased appetite	2/18 (11.1%)
Hyperglycaemia	1/18 (5.6%)
Hypocalcaemia	1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/18 (5.6%)
Myalgia	1/18 (5.6%)
Psychiatric disorders
Insomnia	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	1/18 (5.6%)
Oropharyngeal pain	1/18 (5.6%)
Productive cough	1/18 (5.6%)
Skin and subcutaneous tissue disorders
Rash	6/18 (33.3%)
Dermatitis acneiform	3/18 (16.7%)
Skin fissures	3/18 (16.7%)
Acne	1/18 (5.6%)
Palmar-plantar erythrodysaesthesia syndrome	1/18 (5.6%)
Pruritus generalised	1/18 (5.6%)
Skin exfoliation	1/18 (5.6%)

Limitations/Caveats

No patients met the criteria to enter Part B. Thus planned Part B was not performed in this trial.

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.