Tetracycline as a Prophylaxis for Rash in Patients With NSCLC Receiving Treatment With BIBW2992 (Afatinib)

Study Overview
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Brief Summary
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Advanced NSCLC has a poor prognosis and the positive impact of chemotherapy is limited by the development of intrinsic and acquired resistance. Over the past decade, less toxic agents such as the innovative targeted therapies, i.e. erlotinib or gefitinib, have the potential to improve the effectiveness and keep a good quality of life with a low toxicity BIBW2992 (afatinib), an aniline-quinazoline, is an epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2) irreversible inhibitor, and it has activity against erlotinib-resistant isoforms having mutations in EGFR and HER-2. This molecule has shown benefits as a single agent in pre-treated patients who have progressed despite platinum-based chemotherapy, with a minimal toxicity compared to chemotherapy. BIBW2992 is associated with adverse effects similar to those for erlotinib and gefitinib, such as rash and diarrhea. These symptoms can reduce the quality of life (QL) in patients and lead to inconsistent EGFR inhibitor dose administration There is not a standard treatment for rash. However, case reports have tried to demonstrate the benefit in the treatment of these cutaneous injuries obtained with alcohol-free emollients, sunscreen with titanium dioxide or antibiotic (topic or oral) treatment regimens that include clindamycin or doxycycline, as well as anti-inflammatory drugs such as steroids and isotretinoin. In order to reduce the incidence and severity of cutaneous toxicities, we will compare the prophylactic antibiotic treatment using tetracycline and general dermatological recommendations versus using only dermatological recommendations, in patients initiating the treatment with BIBW2992.

Detailed Description
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Case reports have tried to demonstrate the benefit in the treatment of rash obtained with: alcohol-free emollients used 2-3 times daily, sunscreen with titanium dioxide or zinc oxide with a skin protection factor (SPF) greater than 15, topic or oral antibiotic regimens (such as clindamycin, metronidazole, tetracyclines) when there is secondary infection as well as steroidal anti-inflammatory drugs (betamethasone, triamcinolone) and isotretinoin. The objective of this project is to evaluate whether the prophylactic treatment with tetracycline can reduce dermatological toxicities such as rash, induced by the EGFR and HER-2 tyrosine kinase inhibitor BIBW 2992 in patients with non-small cell lung cancer.

Official Title
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Phase II, Open-label, Single Blind, Randomised Clinical Trial With Tetracycline as a Prophylaxis for Rash and Dermatological Recommendations Versus Dermatological Recommendations in Patients With NSCLC Receiving Treatment With BIBW 2992

Conditions
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Skin Rash, Lung Cancer

Intervention / Treatment
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* Drug: Tetracycline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of non-operable, locally advanced, recurrent or metastatic, histologically or cytologically documented non-small cell lung cancer (stage IIIB or IV). Patients should have an evidence of measurable disease. 18 years or older Eastern Cooperative Oncology Group - Performance Status 0-3 At least 12 weeks of life expectancy Patients with non-small cell lung cancer stages IIIB/IV who have received at least one cycle of platinum-based, first or second line systemic standard chemotherapy, and have a documented failure for this treatment. More than 2 previous chemotherapy regimens are not allowed. The patients should have recovered from any toxic effect and at least 2 weeks should have elapsed from last dose before their entry (14 days for vinorelbine and other vinca alkaloids or gemcitabine). Patients who in the investigator's opinion are fully recovered from surgery for at least 4 weeks may also be considered for the study. Patients should have recovered from any severe toxicity (CTC > 1) caused by any previous therapy. Granulocyte count > 1.5x 109/L and platelet count > 100x 109/L. Serum bilirubin > 1.5 upper limit of normal (ULN) AST and/or ALT > 2 ULN (or >5 x ULN when clearly attributable to presence of hepatic metastases). Serum creatinine > 1.5 ULN or creatinine clearance < 60 mL/min Capability to fulfill the study and follow-up procedures. A negative pregnancy test should be obtained from all women of childbearing potential within 72 hours previous to therapy beginning. Patients of reproductive potential should use effective contraceptive methods. Written (signed) informed consent to participate in the study Exclusion Criteria: Patients allergic to the antibiotic therapy used. Any unsteady systemic disease (including active infection, uncontrolled hypertension, unsteady angina, congestive cardiac failure, hepatic, renal or metabolic disease). A previous treatment using a systemic anti-tumor therapy with EGFR inhibitors (tyrosine kinase inhibitors). Any other malignant pathology within 5 previous years (except for carcinoma in situ of cervix or basal-cell type skin cancer appropriately treated). Patients with cerebral metastases or spinal marrow compression recently diagnosed and/or definitely surgery and/or radiation naïve-treatment patients are excluded. Those with previously diagnosed and treated metastasis to Central Nervous System (CNS) or spinal marrow compression, having an evidence of steady disease (clinically steady in imaging studies) are accepted for at least 2 months. Any significant ophthalmologic abnormality, especially severe dry-eye syndrome, keratoconjunctivitis sicca, Sjögren's syndrome, severe exposure keratitis and any other disorder that may increase the risk for corneal epithelial injure. Contact lens use during the study is not recommended. The decision to continue to use contact lens should be discussed with the oncologist responsible for patient treatment and the ophthalmologist. Patients who cannot take oral medication, requiring intravenous nutrition, who underwent previous surgical procedures affecting absorption, or with active peptic ulcer. Nursing women.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tetracycline<br>Patients will receive tetracycline 250mg every 12 hours for 1 month plus general dermatological recommendations (sunscreen and emollient cream) | Drug: Tetracycline<br>* The experimental group will receive tetracycline 250mg every 12 hours for 1 month the same day at initiation of BIBW2992 whereas the non-intervention group will recieve general dermatological recomendations while on treatment with BIBW2992.<br>* Other names: Tetrex®;|
| No Intervention: No Tetracycline<br>This arm only with general dermatologic recommendations. Patients in this arm can receive tetracycline after week 4 of assessment only if rash grade 3-4 occur | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Participants Who Experienced Any Grade of Rash As Characterized By The Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0 | Sum of participants who experienced any grade rash according to the Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0, from the initiation of BIBW2992 compared to week 8. | Percentage of adverse events at week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life (QoL) | A QoL questionnaire from European Organization for Research and Treatment of Cancer (EORTC) organization (Spanish version) will be performed at initiation of BIBW 2992 and then every month of follow-up until progression | from baseline to 6 months | 
| Progression Free-survival | The measure will be from the start of consumption to the first documented evidence of progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, or if patients still survive the measure will be made after 24 weeks | 24 weeks from baseline | 
| Progression Free Survival | From the start of consumption of BIBW 2992 to the date progression or last follow up | Participants will be followed for the duration of the treatment, an average of 8 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung cancer, BIBW 2992, Skin Rash, Tetracycline, Afatinib