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

Lung Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01880515
• Other study ID #: TEPR-BIBW2992
• Status: Completed
• Phase: Phase 2
• Start date: December 2010
• Est. completion date: November 2014

Study information

• Verified date: April 2023
• Source: Instituto Nacional de Cancerologia de Mexico
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

1. Advanced NSCLC has a poor prognosis and the positive impact of chemotherapy is limited by the development of intrinsic and acquired resistance.

2. 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

3. 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.

4. 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.

5. 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

6. 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.

7. 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 107
• Est. completion date: November 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Exanthema
• Lung Cancer
• Skin Rash

Intervention

Drug:
• Tetracycline
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.

Locations

Country	Name	City	State
Mexico	Instituto Nacional de Cancerología	Mexico City

Sponsors (1)

Lead Sponsor	Collaborator
Instituto Nacional de Cancerologia de Mexico

Country where clinical trial is conducted

Mexico, 

References & Publications (23)

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C. Yang, J. Shih, W. Su, Et.Al. A phase II study of BIBW 2992 in patients with adenocarcinoma of the lung and activating EGFR mutations (LUX-Lung 2).- J Clin Oncol 28: 15s, 2010 (Suppl; Abstr 7521).

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Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005 Feb 24;352(8):786-92. doi: 10.1056/NEJMoa044238. — View Citation

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Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, Settleman J, Tompkins RG, Lynch TJ, Toner M, Haber DA. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008 Jul 24;359(4):366-77. doi: 10.1056/NEJMoa0800668. Epub 2008 Jul 2. — View Citation

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Takezawa K, Okamoto I, Tanizaki J, Kuwata K, Yamaguchi H, Fukuoka M, Nishio K, Nakagawa K. Enhanced anticancer effect of the combination of BIBW2992 and thymidylate synthase-targeted agents in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor. Mol Cancer Ther. 2010 Jun;9(6):1647-56. doi: 10.1158/1535-7163.MCT-09-1009. Epub 2010 Jun 8. — View Citation

Topham E. Cutaneous manifestations of cancer and chemotherapy. Clin Med (Lond). 2009 Aug;9(4):375-9. doi: 10.7861/clinmedicine.9-4-375. No abstract available. — View Citation

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Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007 Jul 1;13(13):3913-21. doi: 10.1158/1078-0432.CCR-06-2610. — View Citation

Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, Ang J, Temple G, Bell S, Shahidi M, Uttenreuther-Fischer M, Stopfer P, Futreal A, Calvert H, de Bono JS, Plummer R. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol. 2010 Sep 1;28(25):3965-72. doi: 10.1200/JCO.2009.26.7278. Epub 2010 Aug 2. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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.