Systemic and Topical Treatments for Rash Secondary to Erlotinib in Lung Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial is to determine if rash caused by erlotinib can be successfully treated and if so to determine the optimal treatment approach. Hypothesis: Hypothesis 1: If the incidence of rash is 50% while on erlotinib, prophylactic monotherapy with minocycline can prevent occurrence in 50% of these patients. Hypothesis 2: Treatment of rash is successful in improving rash by at least one Grade in 80% of patients. Hypothesis 3: In patients with untreated rash, the rash will be self-limiting in 25% of patients, and 65% will be grade 1, 2A, and 2b. Ten percent will be grade 3 requiring treatment with monotherapy intervention.

Detailed Description
-----------------
Erlotinib has been shown to prolong survival in NSCLC patients who are no longer candidates for further chemotherapy. In July 2005, erlotinib was approved in Canada for the treatment of patients with locally advanced or metastatic NSCLC, following failure of first or second-line chemotherapy. Erlotinib's side effect profile includes rash. The incidence of rash in clinical trials has been reported to be approximately 50 - 75%, and has been hypothesised to parallel tumour response (20). The treatment of rash is controversial and many oncologists believe it is untreatable and self-limiting. The cause of the rash is not well understood but is felt to be a systemic event. Clinical experience of the investigators has suggested that minocycline 100 mg orally given twice-daily for 4 weeks and clindamycin 2% and hydrocortisone 1% topical cream for moderate to severe rash is a successful treatment. The objectives of this trial are to better delineate the rash and its features and to describe an optimal treatment. Since the rash is often facial in distribution and can therefore lead to physical and psychological distress to the patient, a dermatology life quality index will also be completed throughout the study.

Official Title
-----------------
A Randomized Controlled Trial of Systemic and Topical Treatments for Rash Secondary to Erlotinib in Advanced Stage IIIB or IV Non-Small Cell Lung Cancer

Conditions
-----------------
Rash

Intervention / Treatment
-----------------
* Drug: Minocycline
* Drug: Clindamycin 2% in hydrocortisone 1% lotion
* Drug: Erlotinib
* Drug: Topical clindamycin 2%, triamcinolone acetonide 0.1% soln


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytological documented diagnosis of inoperable, locally advanced, recurrent or metastatic (stage IIIB or stage IV) non-small cell lung cancer. Evidence of disease (measurable disease is not mandatory). 18 years of age or older. ECOG performance status of 0 - 3. Written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice. Exclusion Criteria: A history of another cancer other than basal cell carcinoma or cervical cancer in situ within the past 3 years Prior therapy with any type of cancer growth factor inhibitor (EGFR inhibitor or agent targeting this family of growth factor receptors) Life expectancy of less than 12 weeks. Ongoing toxic effects from prior chemotherapy. Pregnant or lactating women. Females of childbearing potential who have a positive or no pregnancy test (pregnancy tests must be obtained within 72 hours before starting therapy). (Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential). Male or female patients with reproductive potential who are unwilling to use effective and reliable contraceptive methods throughout the course of the study and for 90 days after the last dose of study medication. Ongoing treatment with any inhibitors or inducers of CYP3A4 activity Any unstable systemic disease (including active infection, grade 4 hypertension, unstable angina, congestive heart failure, hepatic, renal or metabolic disease). Any significant ophthalmologic abnormality, especially severe dry eye syndrome, keratoconjunctivitis sicca, Sjögren syndrome, severe exposure keratitis or any other disorder likely to increase the risk of corneal epithelial lesions. Unwilling or unable to comply with the protocol for the duration of the study. Patients who have experienced prior hypersensitivity reaction to active ingredients or excipients of the following compounds: erlotinib, minocycline, tetracycline, doxycycline or clindamycin.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Prophylactic Treatment<br>Participants will receive prophylactic treatment with minocycline 100 mg orally twice-daily for at least 4 weeks on the initiation of erlotinib therapy. If rash occurs during the 4 week period of minocycline prophylaxis, the minocycline prophylaxis will continue and additional treatment by grade of rash will be according to the Treatment Arm 2 schedule. If rash occurs after the completion of the 4 week prophylaxis period, treatment by grade of rash will be according to the Treatment Arm 2 schedule. | Drug: Minocycline<br>* Patients will receive prophylactic treatment with minocycline 100 mg orally twice-daily for at least 4 weeks on the initiation of erlotinib therapy. If rash occurs during the 4 week period of minocycline prophylaxis, the minocycline prophylaxis will continue and additional treatment by grade of rash will be according to the Treatment Arm 2 schedule. If rash occurs after the completion of the 4 week prophylaxis period, treatment by grade of rash will be according to the Treatment Arm 2 schedule.<br>* Other names: Myrac;Drug: Clindamycin 2% in hydrocortisone 1% lotion<br>* Appropriate amounts of clindamycin and hydrocortisone powder are mixed with corresponding amount of Nutraderm® lotion for this mixture. If preferred, the appropriate amount of clindamycin powder can be mixed with Emo-Cort® lotion (already contains hydrocortisone 1%), available in 60 mL bottles.<br>Drug: Erlotinib<br>* Erlotinib will be given on an outpatient basis at a fixed dose of either 150 or 100 mg as a single daily oral dose.<br>* Other names: Tarceva;Drug: Topical clindamycin 2%, triamcinolone acetonide 0.1% soln<br>* Clindamycin 2% in Triamcinolone acetonide 0.1% solution in equal parts propylene glycol and water<br>|
| Experimental: Arm 2: Reactive Treatment<br>Pts will receive treatment at initiation of rash. Tx is dependent on grading of rash as follows: Grade 1 or 2A: Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice daily until resolution of rash by one grade Grade 2B: Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied 2x daily and oral minocycline 100mg 2x daily for a min. of 4 weeks and continuing thereafter, as required, until resolution of rash by 1 grade. Scalp lesions will be treated with a topical clindamycin 2%, triamcinolone acetonide 0.1% soln. Grade 3: Pts will discontinue tx with erlotinib 150mg for 1 week and restart at 100mg once daily. Tx with topical clindamycin 2%, with hydrocortisone 1% in lotion base applied 2x daily and oral minocycline 100mg 2x daily for a min. of 4 weeks and continuing thereafter, as required, until resolution of rash to Grade 1 or 2A. Scalp lesions will be treated with a topical clindamycin 2%, triamcinolone acetonide 0.1% soln. | Drug: Minocycline<br>* Patients will receive prophylactic treatment with minocycline 100 mg orally twice-daily for at least 4 weeks on the initiation of erlotinib therapy. If rash occurs during the 4 week period of minocycline prophylaxis, the minocycline prophylaxis will continue and additional treatment by grade of rash will be according to the Treatment Arm 2 schedule. If rash occurs after the completion of the 4 week prophylaxis period, treatment by grade of rash will be according to the Treatment Arm 2 schedule.<br>* Other names: Myrac;Drug: Clindamycin 2% in hydrocortisone 1% lotion<br>* Appropriate amounts of clindamycin and hydrocortisone powder are mixed with corresponding amount of Nutraderm® lotion for this mixture. If preferred, the appropriate amount of clindamycin powder can be mixed with Emo-Cort® lotion (already contains hydrocortisone 1%), available in 60 mL bottles.<br>Drug: Erlotinib<br>* Erlotinib will be given on an outpatient basis at a fixed dose of either 150 or 100 mg as a single daily oral dose.<br>* Other names: Tarceva;Drug: Topical clindamycin 2%, triamcinolone acetonide 0.1% soln<br>* Clindamycin 2% in Triamcinolone acetonide 0.1% solution in equal parts propylene glycol and water<br>|
| Experimental: Arm 3: No Treatment Unless Severe (Grade 3)<br>This is the control group. Patients will be treated only if grade 3 rash develops. For grade 3 rash, treatment will be in accordance with that of Grade 3 rash in Treatment Arm 2. | Drug: Minocycline<br>* Patients will receive prophylactic treatment with minocycline 100 mg orally twice-daily for at least 4 weeks on the initiation of erlotinib therapy. If rash occurs during the 4 week period of minocycline prophylaxis, the minocycline prophylaxis will continue and additional treatment by grade of rash will be according to the Treatment Arm 2 schedule. If rash occurs after the completion of the 4 week prophylaxis period, treatment by grade of rash will be according to the Treatment Arm 2 schedule.<br>* Other names: Myrac;Drug: Clindamycin 2% in hydrocortisone 1% lotion<br>* Appropriate amounts of clindamycin and hydrocortisone powder are mixed with corresponding amount of Nutraderm® lotion for this mixture. If preferred, the appropriate amount of clindamycin powder can be mixed with Emo-Cort® lotion (already contains hydrocortisone 1%), available in 60 mL bottles.<br>Drug: Erlotinib<br>* Erlotinib will be given on an outpatient basis at a fixed dose of either 150 or 100 mg as a single daily oral dose.<br>* Other names: Tarceva;Drug: Topical clindamycin 2%, triamcinolone acetonide 0.1% soln<br>* Clindamycin 2% in Triamcinolone acetonide 0.1% solution in equal parts propylene glycol and water<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Incidence of Rash | The overall incidence of any grade of erlotinib-induced rash among the three treatment arms. For overall incidence of rash a binary variable will be designed. Data will be summarized with percentages by treatment group. | From onset of rash until resolution, up to 4 weeks following progression, an average of 1 year | 
| Time Duration From Onset of Rash Until Resolution | To investigate if the rash caused by erlotinib is self-limiting. A time variable will be defined to identify the duration from onset of rash until resolution. Resolution will be defined as resolution to severity Grade 1 for patients with rash of maximum severity grade >1 and resolution to Grade 0 for patients with maximum rash severity = 1. For patients where resolution is not observed the time considered will be the maximum time from onset of rash until end of the study. The analyses will be performed using the following two sub-populations: subjects with maximum severity of rash of Grade 1, 2a and 2b will constitute one sub-population and Grade 3 will be considered the second sub-population. The comparisons will be performed primarily for Group 1 vs. Group 3 and Group 2 vs. Group 3 and secondly for Group 1 vs. Group 2. | From onset of rash until resolution, up to 4 weeks following progression, an average of 1 year | 
| Overall Incidence of Grade 3 Rash | The overall incidence of grade 3 erlotinib-induced rash among the three treatment arms. For overall incidence of rash a binary variable will be designed. Data will be summarized with percentages by treatment group. | From onset of rash until resolution, up to 4 weeks following progression, on average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Rash Caused by Erlotinib | The maximum severity of rash per subject will be summarized by treatment group. The summary will include only subjects who indicated any occurrence of rash. | Onset until resolution, up to 4 weeks following progression, on average of 1 year | 
| Overall Survival |  | Until death | 
| Duration of Treatment |  | Up to one year | 
| Time to First Presentation of Rash |  | Up to onset of rash while on study treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rash, Erlotinib, Lung Cancer