A Study of Management of Tarceva - Induced Rash in Patients With Non-Small Cell Lung Cancer.

Study Overview
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Brief Summary
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This 2 arm study will evaluate the management of Tarceva-induced skin rash in patients with non-small cell lung cancer who have failed first-line chemotherapy for advanced disease. Eligible patients will be randomized to receive a)doxycycline 100mg po daily or b)no preventative treatment; all patients will receive Tarceva 150mg/kg po daily. The anticipated time on study treatment is until disease progression or intolerable toxicity, and the target sample size is 100-500 individuals.

Official Title
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A Randomized, Open Label Study to Evaluate the Effect of Doxycycline on Tarceva-induced Skin Rash in Patients With Non-small Cell Lung Cancer After Failure of First Line Chemotherapy

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Doxycline
* Drug: erlotinib [Tarceva]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, 18-75 years of age; confirmed non-small cell lung cancer; failure after first line chemotherapy for advanced disease, and scheduled for second line therapy with Tarceva. Exclusion Criteria: rash of any etiology at study entry; history of significant heart disease; any other malignancies (other than adequately treated squamous cell skin cancer, or in situ cancer of the cervix); history of allergic reactions to tetracyclines.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Doxycline<br>* 100mg po daily<br>Drug: erlotinib [Tarceva]<br>* 150mg po daily<br>|
| Active Comparator: 2<br> | Drug: erlotinib [Tarceva]<br>* 150mg po daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least One Skin Rash (Folliculitis) of Any Grade During the First 4 Months of Treatment | Description of skin rash (folliculitis, including erythema, papulo-pustules, nodule, and crust) was according to Common Terminology Criteria for Adverse Events (CTCAE) version 3 scale. Medical pictures of the face (front and sides views) systematically, and of any region presenting with skin lesions were obtained. The pictures were reviewed by a centralized committee of evaluation. | Days 0, 14, 28 and Months 2, 3, and 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Skin Rash (Folliculitis) Events During the First 4 Months of Treatment | A cutaneous rash as folliculitis can be defined with several types including erythema, papulo-pustular and nodules. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Percentage of Participants With Skin Rash (Folliculitis) During the First 4 Months of Treatment By Type | A cutaneous rash as folliculitis can be defined with several types including erythema, papulo-pustule, nodule, and crust. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Percentage of Participants With Skin Rash (Folliculitis) During the First 4 Months of Treatment By Maximal Intensity | Intensity of skin rashes was classified according to CTCAE grading. Grade 1 equals (=) Macular or papular eruption or erythema without associated symptoms; Grade 2=Macular or papular eruption or erythema with pruritus or other associated symptoms; localized desquamation or other lesions covering less than (<)50 percent (%) of body surface area (BSA); Grade 3=Severe, generalized erythroderma or macular, papular, or vesicular eruption; desquamation. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Percentage of Participants With at Least One Skin Rash (Folliculitis) of Any Grade After the First 4 Months of Treatment |  | Months 7, 10, and 12 | 
| Number of Skin Rash (Folliculitis) Events After the First 4 Months of Treatment | A cutaneous rash as folliculitis can be defined with several types including erythema, papulo-pustular and nodules. | Months 7, 10, and 12 | 
| Number of Participants With Skin Rash (Folliculitis) After the First 4 Months of Treatment By Type | A cutaneous rash as folliculitis can be defined with several types including erythema, papulo-pustule, nodule, and crust. | Months 7, 10, and 12 | 
| Number of Participants With Skin Rash (Folliculitis) After the First 4 Months of Treatment By Intensity | Intensity of skin rashes was classified according to CTCAE grading. Grade 1=Macular or papular eruption or erythema without associated symptoms; Grade 2=Macular or papular eruption or erythema with pruritus or other associated symptoms; localized desquamation or other lesions covering <50% of BSA; Grade 3=Severe, generalized erythroderma or macular, papular, or vesicular eruption; desquamation. | Months 7, 10, and 12 | 
| Time Free From Skin Rash (Folliculitis) During the First 4 Months of Treatment - Number of Participants With an Event | Period without occurrence was determined as the number of days from the first dose of medication until the first appearance of folliculitis, analyzed using Kaplan-Meier analysis. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Time Free From Skin Rash (Folliculitis) During the First 4 Months of Treatment - Time to Event | Period without occurrence was determined as the number of days from the first dose of medication until the first appearance of folliculitis, analyzed using Kaplan-Meier analysis. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Percentage of Participants Estimated to be Event Free at 4 Months | Percentage of participants estimated to be without skin rash (folliculitis) at 4 months. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Time Free From Skin Rash (Folliculitis) During the Whole Treatment Period - Number of Participants With an Event | Period without occurrence was determined as the number of days from the first dose of medication until the first appearance of folliculitis, analyzed using Kaplan-Meier analysis. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Time Free From Skin Rash (Folliculitis) During the Whole Treatment Period - Time to Event | Period without occurrence was determined as the number of days from the first dose of medication until the first appearance of folliculitis, analyzed using Kaplan-Meier analysis. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Percentage of Participants Estimated to be Event Free at 12 Months | Percentage of participants estimated to be without skin rash (folliculitis) at 12 months. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Duration of Skin Rash (Folliculitis) During the First 4 Months of Treatment | If the cutaneous rash was ongoing at the last visit or Month 4, the duration of cutaneous rash was calculated between start of folliculitis and Visit Month 4 or premature withdrawal visit or death. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Duration of Skin Rash (Folliculitis) During the Whole Treatment Period | If the end of cutaneous rash was missing, the duration of cutaneous rash was calculated between start of folliculitis and last evaluation date. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Percentage of Participants With Other Skin Lesions of Any Grade During the First 4 Months of Treatment | Other skin lesions included presence or absence of xerosis and paronychia. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Percentage of Participants With Other Skin Lesions During the First 4 Months of Treatment By Type | Other skin lesions included xerosis and paronychia. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Percentage of Participants With Other Skin Lesions During the First 4 Months of Treatment By Maximal Intensity | Other skin lesions included xerosis and paronychia. Intensity was classified according to CTCAE grading. Grade 1=Macular or papular eruption or erythema without associated symptoms; Grade 2=Macular or papular eruption or erythema with pruritus or other associated symptoms; localized desquamation or other lesions covering <50% of BSA; Grade 3=Severe, generalized erythroderma or macular, papular, or vesicular eruption; desquamation; Grade 4=Generalized exfoliative, ulcerative, or bullous dermatitis. If a participant had several skin lesions, the maximal intensity was taken into account. | Days 0, 14, 28 and Months 2, 3, and 4 | 
| Percentage of Participants With Erlotinib Dose Reduction by Reason for Reduction | Erlotinib dose adjustment was done in case of toxicity occurrence. Keratitis, diarrhea, interstitial lung disease, and other toxic occurrences determined erlotinib dose reduction. If erlotinib was previously discontinued for skin rash or diarrhea of Grade 2 and if these symptoms of Grade 2 recurred OR if the symptoms were intolerable for the participants, erlotinib was discontinued until recovery/Grade 1 then the dose was reduced of one level of 50 mg. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Percentage of Participants With Doxycycline Dose Reduction by Reason for Reduction | Occurrence of folliculitis-type skin rash of Grade greater than or equal to (≥)2 led to dose modification. Continuation of treatment with doxycycline after occurrence of folliculitis-type skin rash of Grade ≥2 was upon the investigator's opinion. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Percentage of Participants With Global Disease Control by Visit | Disease control was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria for evaluation and was defined as participants with either complete response (CR), partial response (PR), or stable disease (SD). | Months 2, 4, 7, 10, and 12 | 
| Percentage of Participants by Best Global Response Under Treatment | Response was determined according to the RECIST criteria for evaluation and was defined as participants with either CR, PR, SD, or progression. No CR was reported. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Progression-Free Survival (PFS) - Percentage of Participants With an Event | PFS was defined by the time between first intake of treatment with erlotinib and disease progression or death for any cause; estimated using Kaplan-Meier method. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Progression-Free Survival (PFS) - Time to Event | PFS was defined by the time between first intake of treatment with erlotinib and disease progression or death for any cause; estimated using Kaplan-Meier method. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Percentage of Participants Estimated to be Progression Free at 4 and 12 Months |  | Months 4 and 12 | 
| Overall Survival (OS) - Percentage of Participants With an Event | OS was defined by the time between first intake of treatment with erlotinib and death for any cause; analyzed using Kaplan-Meier method. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Overall Survival (OS) - Time to Event | OS was defined by the time between first intake of treatment with erlotinib and death for any cause; analyzed using Kaplan-Meier method. | Days 0, 14, 28 and Months 2, 3, 4, 7, 10, and 12 | 
| Percentage of Participants Estimated to be Alive at 4 and 12 Months |  | Months 4 and 12 | 
| Dermatology Life Quality Index (DLQI) Global Score | Quality of life was assessed by participant's responses to a DLQI questionnaire. The DLQI is a 10-item questionnaire assessing quality of life; questions were assessed on a 4-point scale (0=not at all; 1=a little; 2=a lot; and 3=very much). The DLQI was calculated by summing the score of each question resulting in a maximum of 30 (extremely large effect on participant's life) and a minimum of 0 (no effect at all on participant's life). The higher the score, the more quality of life is impaired. Analysis was performed by visit well as at the last available value after baseline (Endpoint); change from baseline to endpoint was also determined. | Baseline, Days 14 and 28 and Months 2, 3, and 4 | 
| Percentage of Participants by DLQI Global Score Classification of Disease Effect on Quality of Life | Quality of life was assessed by participant's responses to a DLQI questionnaire. The DLQI is a 10-item questionnaire assessing quality of life; questions were assessed on a 4-point scale (0=not at all; 1=a little; 2=a lot; and 3=very much). The DLQI was calculated by summing the score of each question resulting in a maximum of 30 (extremely large effect on participant's life) and a minimum of 0 (no effect at all on participant's life). The higher the score, the more quality of life is impaired. The DLQI global score was classified into 5 levels: 0-1 (no effect at all), 2-5 (small effect), 6-10 (moderate effect), 11-20 (very large effect) and 21-30 (extremely large effect). | Baseline, Days 14 and 28 and Months 2, 3, and 4 | 
| Quality of Life Score as Assessed by Visual Analog Scale (VAS) | Quality of life was assessed by participant's responses to a VAS questionnaire - (evaluation of satisfaction with skin status). VAS was measured on a 100 millimeter (mm) scale where 0 = not at all satisfied and 100 = very satisfied. Participants were asked to mark the line corresponding to their satisfaction at each visit and the distance from the left edge was measured. A negative change from baseline indicates improvement. Analysis was performed by visit well as at the last available value after baseline (Endpoint). | Baseline, Days 14 and 28, and Months 2, 3, and 4 |