Afatinib in NSCLC With HER2 Mutation

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

Official Title
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A Phase II Study of Afatinib in Patients With Advanced NSCLC Harboring HER2 Mutations, Previously Treated With Chemotherapy

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: afatinib
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: all patients<br>Part A: all enrolled patients will receive afatinib monotherapy. Part B: all eligible patients will receive afatinib combined with weekly paclitaxel. | Drug: afatinib<br> <br> Drug: paclitaxel<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Objective Response (OR) in Part A According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Disease Control (DC) in Part A | 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. | 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 | 
| Progression Free Survival (PFS) in Part A | 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. | 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 | 
| Overall Survival (OS) | 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. | From start of treatment of afatinib until death from any cause, ie up to approximately 12 Months | 
| Time to Progression (TTP) in Part A | 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. | From the date of starting treatment of afatinib to the date of disease progression , ie up to approximately 12 Months | 
| Duration of Response (DOR) in Part A | 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. | 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 |