Afatinib in NSCLC With HER2 Mutation

Study Overview
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Brief Summary
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The purpose of this study is to investigate the control of disease in pretreated patients with advanced non small cell lung cancer (NSCLC) harbouring HER2 exon 20 mutations as well as the safety and tolerability (how severe the side effects are) of the treatment with afatinib.

Detailed Description
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Previous clinical studies of NSCLC have shown that patients with tumors harboring specific gene mutations (changes) in the epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) showed better results after treatment with tyrosine kinase inhibitors (TKI), like afatinib (tradename Giotrif®) , compared with classical treatment with chemotherapy. The treatment with TKI has become a new standard-of-care for patient with advanced lung cancer and EGFR or ALK changes. Several novel mutations, which are candidates as targets for specific medication have been discovered. Human epidermal growth factor 2 (HER2, erbB-2/neu) is a protein of the so called ErbB family (including HER2 [ErbB2], ErbB3 and ErbB4). These proteins are involved in the growth and spread of cancer cells. Mutations in HER2 are found in about 2% of the NSCLC. Afatinib works by blocking the activity of the ErbB family proteins and can inhibit growth and spread of cancer cells. Afatinib is approved by the European and the Swiss Medicines Agencies for the treatment of adult patients with a specific type of cancer of the lung (non-small cell lung cancer) that is identified by a change (mutation) in the gene for EGFR as first treatment or if prior chemotherapy treatment has been insufficient. A total of 22 patients from centers around Europe are expected to be enrolled in this study over a period of 24 months. All patients will be treated in the same way. The study will take approximately 40 months to be completed. This clinical trial is conducted according to the applicable national laws and international guidelines.

Official Title
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Afatinib in Pretreated Patients With Advanced NSCLC Harbouring HER2 Exon 20 Mutations

Conditions
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NSCLC

Intervention / Treatment
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* Drug: Afatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed non small cell lung cancer Stage IIIB (non amenable to curative-intent multimodal treatment) or IV NSCLC, according to 7th TNM classification. Contrast-enhanced CT of thorax and upper abdomen (incl. liver, kidney, adrenals); brain MRI or CT within 28 days before the date of enrolment. Non-predominant squamous subtype (<50% squamous cells). Previous treatment with a platinum based chemotherapy for advanced disease; or Disease relapse or progression within <6 months after adjuvant platinum based chemotherapy, or (definitive) platinum-based chemo(radio)therapy for stage I-III NSCLC Measurable or evaluable disease (according to RECIST 1.1 criteria). Not eligible: patients with only one measurable or evaluable tumour lesion which was resected or irradiated prior to enrolment. Locally documented HER2 mutation Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Life expectancy >3 months. Adequate haematological function: WBC ≥ 2000/μL haemoglobin ≥ 9 g/dL neutrophils count ≥1.5×109/L platelet count ≥ 100 × 109/L Adequate liver function: Total bilirubin ≤ 1.5 × ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) ALT < 2.5 × ULN AST < 2.5 × ULN GGT < 2.5 × ULN. Adequate renal function: Calculated creatinine clearance ≥ 45mL/min (Cockroft-Gault) Patient capable of proper therapeutic compliance, and accessible for correct followup. Women of childbearing potential (< 1 year without menstruation or < 2 years without menstruation following chemotherapy) must have a negative serum or urine pregnancy test within 7 days before beginning trial treatment. Sexually active men and women of childbearing potential must use an effective contraceptive method (two barrier methods or a barrier method plus a hormonal method) during the trial treatment and for a period of at least 28 days following the last administration of trial drug. Recovered from any previous therapy related toxicity to ≤Grade 1 at date of enrolment (except for recovery to ≤Grade 2 of alopecia, fatigue, creatinine increased, lack of appetite as well as stable sensory neuropathy) Written Informed Consent (IC) for trial treatment must be signed and dated by the patient and the investigator prior to any trial-related intervention. Tumour block available for central review of HER2 mutation status. Exclusion Criteria: Patient with mixed small-cell and non-small-cell histologic features Uncontrolled lepto-meningeal metastatic disease. Radiotherapy-treated or asymptomatic brain metastases are allowed (no systematic screening). Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids or have been on stable dose of corticosteroids for at least 4 weeks before starting trial treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before date of enrolment. Previous treatment with HER2 targeted antibody or tyrosine kinase inhibitor including afatinib. Major surgery within 4 weeks before starting trial treatment or scheduled for surgery during the projected course of the trial. Patient who has had in the past 3 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of III or IV (see Table 2 below), unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior to enrolment. Patient with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical processes that could affect the patient's capacity to participate in the trial. Known HIV, active Hepatitis B or Hepatitis C infection (screening not required). Known or suspected hypersensitivity to afatinib or any of its excipients. Interstitial lung disease or pulmonary fibrosis. Women who are pregnant or in the period of lactation. Patients with any concurrent systemic anticancer therapy. Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the trial drug (e.g. Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption. Patient who received treatment with an investigational drug agent during the 3 weeks before enrolment in the trial.

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 |
| --- | --- |
| Other: Afatinib<br>Afatinib 40 mg p.o./day until tumour progression or lack of tolerability | Drug: Afatinib<br>* 40mg p.o./ day until documented progression or unacceptable toxicity<br>* Other names: BIBW 2992;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control (Defined as Complete or Partial Response, or Disease Stabilisation Lasting at Least 12 Weeks) | Disease control (DC) is defined as complete or partial response, or disease stabilisation lasting at least 12 weeks. Disease control will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions denotes disease progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial. | at interim (after the first 9 pts have been followed for 12 weeks) & final analysis (approx. 40 months after inclusion of first pt) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival (PFS) is defined as the time from date of enrollment until documented progression or death, if progression is not documented. Censoring will occur at the last tumor assessment only if patients is lost to follow-up | Time assessed from the date of enrolment until documented progression or death (max 36 months) | 
| Objective Response | Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response to afatinib treatment will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions denotes disease progression. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial. | Assessed across all time-points during the period from enrolment to termination of trial treatment (max. 36 months) | 
| Overall Survival | Overall survival (OS) is defined as the time from the date of enrollment until death from any cause. Censoring will occur at the last follow-up. | Time assessed from the date of enrolment until death (max 36 months) | 
| Toxicities of Treatment | Adverse events classified according to NCI CTCAE version 4. | Assessed from the date of informed consent until 90 days after the final dose of afatinib (max 18 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage IIIb/ IV NSCLC harbouring HER2 exon 20 mutations