Rash
Conditions
Keywords
Rash, Erlotinib, Lung Cancer
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.
Interventions
DRUGMinocycline
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.
DRUGClindamycin 2% in hydrocortisone 1% lotion
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.
DRUGErlotinib
Erlotinib will be given on an outpatient basis at a fixed dose of either 150 or 100 mg as a single daily oral dose.
DRUGTopical clindamycin 2%, triamcinolone acetonide 0.1% soln
Clindamycin 2% in Triamcinolone acetonide 0.1% solution in equal parts propylene glycol and water
Sponsors
Hoffmann-La Roche
British Columbia Cancer Agency
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytological documented diagnosis of inoperable, locally advanced, recurrent or metastatic (stage IIIB or stage IV) non-small cell lung cancer. 2. Evidence of disease (measurable disease is not mandatory). 3. 18 years of age or older. 4. ECOG performance status of 0 - 3. 5. 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
1. A history of another cancer other than basal cell carcinoma or cervical cancer in situ within the past 3 years 2. Prior therapy with any type of cancer growth factor inhibitor (EGFR inhibitor or agent targeting this family of growth factor receptors) 3. Life expectancy of less than 12 weeks. 4. Ongoing toxic effects from prior chemotherapy. 5. Pregnant or lactating women. 6. 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). 7. 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. 8. Ongoing treatment with any inhibitors or inducers of CYP3A4 activity 9. Any unstable systemic disease (including active infection, grade 4 hypertension, unstable angina, congestive heart failure, hepatic, renal or metabolic disease). 10. 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. 11. Unwilling or unable to comply with the protocol for the duration of the study. 12. Patients who have experienced prior hypersensitivity reaction to active ingredients or excipients of the following compounds: erlotinib, minocycline, tetracycline, doxycycline or clindamycin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Incidence of Rash | From onset of rash until resolution, up to 4 weeks following progression, an average of 1 year | 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. |
| Time Duration From Onset of Rash Until Resolution | From onset of rash until resolution, up to 4 weeks following progression, an average of 1 year | 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. |
| Overall Incidence of Grade 3 Rash | From onset of rash until resolution, up to 4 weeks following progression, on average of 1 year | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severity of Rash Caused by Erlotinib | Onset until resolution, up to 4 weeks following progression, on average of 1 year | 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. |
| Time to First Presentation of Rash | Up to onset of rash while on study treatment | — |
| Overall Survival | Until death | — |
| Duration of Treatment | Up to one year | — |
Countries
Canada
Participant flow
Recruitment details
Eligible patients had a histological or cytologic documented diagnosis of metastatic NSCLC, with and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3. The study was initiated on November 7, 2008, and concluded with the last patient in December 2012.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Prophylactic Treatment Subjects (approximately 50) will be given minocycline (an antibiotic pill) 100mg orally to take for 4 weeks at the same time as starting their erlotinib to see if the rash can be prevented
minocycline: Arm 1: Subjects (approximately 50) will be given minocycline (an antibiotic pill) 100mg orally to take for 4 weeks at the same time as starting their erlotinib to see if the rash can be prevented. If rash occurs then subjects will be treated using a medicated lotion, (clindamycin 2% and hydrocortisone 1%,) to be applied to the rash and if the rash is more severe, minocycline may be continued for more than 4 weeks. | 50 |
| Arm 2: Reactive Treatmen Arm 2: Subjects (Approximately 50) will be treated for the rash caused by erlotinib when it develops and the treatment will be a medicated lotion, (clindamycin 2% and hydrocortisone 1%,), applied to the rash and if the rash is more severe, minocycline 100mg orally twice daily. Scalp lesions will be treated with a topical clindamycin 2 %, triamcinolone acetonide 0.1% solution.
minocycline; Lotion (clindamycin 2% /hydrocortisone 1%): Subjects (Approximately 50) will be treated for the rash caused by erlotinib when it develops and the treatment will be a medicated lotion, (clindamycin 2% and hydrocortisone 1%,), applied to the rash and if the rash is more severe, minocycline 100mg orally twice daily. Scalp lesions will be treated with a topical clindamycin 2 %, triamcinolone acetonide 0.1% solution | 50 |
| Arm 3: No Treatment Unless Severe (Grade 3) Arm 3: Subjects (Approximately 50) that develop the rash caused by erlotinib will only be treated if their rash becomes severe to see if it will go away itself. The treatment for severe rash will be medicated lotion, (clindamycin 2% and hydrocortisone 1%,), applied to the rash and minocycline 100mg orally twice daily. Scalp lesions will be treated with a topical clindamycin 2 %, triamcinolone acetonide 0.1% solution
clindamycin 2% and hydrocortisone 1%,: Arm 3: Subjects (Approximately 50) that develop the rash caused by erlotinib will only be treated if their rash becomes severe to see if it will go away itself. The treatment for severe rash will be medicated lotion, (clindamycin 2% and hydrocortisone 1%,), applied to the rash and minocycline 100mg orally twice daily. Scalp lesions will be treated with a topical clindamycin 2 %, triamcinolone acetonide 0.1% solution. | 50 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Arm 1: Prophylactic Treatment | Arm 2: Reactive Treatmen | Arm 3: No Treatment Unless Severe (Grade 3) | Total |
|---|---|---|---|---|
| Age, Continuous | 64.3 years | 65.9 years | 64.4 years | 64.9 years |
| Region of Enrollment Canada | 50 participants | 50 participants | 50 participants | 150 participants |
| Sex: Female, Male Female | 17 Participants | 27 Participants | 27 Participants | 71 Participants |
| Sex: Female, Male Male | 33 Participants | 23 Participants | 23 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 49 | 1 / 50 | 5 / 50 |
| serious Total, serious adverse events | 1 / 49 | 0 / 50 | 0 / 50 |
Outcome results
Primary
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.
Time frame: From onset of rash until resolution, up to 4 weeks following progression, on average of 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Prophylactic Treatment | Overall Incidence of Grade 3 Rash | 14.3 percentage of participants |
| Arm 2: Reactive Treatment | Overall Incidence of Grade 3 Rash | 9.5 percentage of participants |
| Arm 3: No Treatment Unless Severe (Grade 3) | Overall Incidence of Grade 3 Rash | 34.1 percentage of participants |
Primary
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.
Time frame: From onset of rash until resolution, up to 4 weeks following progression, an average of 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Prophylactic Treatment | Overall Incidence of Rash | 84 percentage of participants |
| Arm 2: Reactive Treatment | Overall Incidence of Rash | 84 percentage of participants |
| Arm 3: No Treatment Unless Severe (Grade 3) | Overall Incidence of Rash | 82 percentage of participants |
p-value: 0.8769Chi-squared
p-value: 0.147Wilcoxon (Mann-Whitney)
Primary
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.
Time frame: From onset of rash until resolution, up to 4 weeks following progression, an average of 1 year
Population: Patients With Maximum Severity of Rash Grade 1, 2b: Arm 1 (n=36), Arm 2 (n=38), Arm 3 (n=27)~Patients With Maximum Severity of Rash Grade 3: Arm 1 (n=6), Arm 2 (n=4), Arm 3 (n=14)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1: Prophylactic Treatment | Time Duration From Onset of Rash Until Resolution | Patients With Max Severity of Rash Gr 1, 2a and 2b | 133.0 days |
| Arm 1: Prophylactic Treatment | Time Duration From Onset of Rash Until Resolution | Patients With Maximum Severity of Rash Grade 3 | 201.0 days |
| Arm 2: Reactive Treatment | Time Duration From Onset of Rash Until Resolution | Patients With Max Severity of Rash Gr 1, 2a and 2b | 92.0 days |
| Arm 2: Reactive Treatment | Time Duration From Onset of Rash Until Resolution | Patients With Maximum Severity of Rash Grade 3 | 76.0 days |
| Arm 3: No Treatment Unless Severe (Grade 3) | Time Duration From Onset of Rash Until Resolution | Patients With Max Severity of Rash Gr 1, 2a and 2b | 98.0 days |
| Arm 3: No Treatment Unless Severe (Grade 3) | Time Duration From Onset of Rash Until Resolution | Patients With Maximum Severity of Rash Grade 3 | 54.0 days |
p-value: 0.1503Wilcoxon (Mann-Whitney)
p-value: 0.4681Wilcoxon (Mann-Whitney)
p-value: 0.0196Wilcoxon (Mann-Whitney)
p-value: 0.1658Wilcoxon (Mann-Whitney)
p-value: >0.9999Wilcoxon (Mann-Whitney)
p-value: 0.285Wilcoxon (Mann-Whitney)
Secondary
Duration of Treatment
Time frame: Up to one year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Prophylactic Treatment | Duration of Treatment | 3.6 months |
| Arm 2: Reactive Treatment | Duration of Treatment | 1.8 months |
| Arm 3: No Treatment Unless Severe (Grade 3) | Duration of Treatment | 1.8 months |
Secondary
Overall Survival
Time frame: Until death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Prophylactic Treatment | Overall Survival | 7.6 months |
| Arm 2: Reactive Treatment | Overall Survival | 8.0 months |
| Arm 3: No Treatment Unless Severe (Grade 3) | Overall Survival | 6.0 months |
p-value: 0.3834Log Rank
Secondary
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.
Time frame: Onset until resolution, up to 4 weeks following progression, on average of 1 year
Population: Arm 1 (n=42), Arm 2 (n=42), Arm 3, (n=41)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: Prophylactic Treatment | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 1 | 40.5 percentage of participants |
| Arm 1: Prophylactic Treatment | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 2a | 26.2 percentage of participants |
| Arm 1: Prophylactic Treatment | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 2b | 19.0 percentage of participants |
| Arm 1: Prophylactic Treatment | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 3 | 14.3 percentage of participants |
| Arm 2: Reactive Treatment | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 3 | 9.5 percentage of participants |
| Arm 2: Reactive Treatment | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 1 | 47.6 percentage of participants |
| Arm 2: Reactive Treatment | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 2b | 9.5 percentage of participants |
| Arm 2: Reactive Treatment | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 2a | 33.3 percentage of participants |
| Arm 3: No Treatment Unless Severe (Grade 3) | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 3 | 34.1 percentage of participants |
| Arm 3: No Treatment Unless Severe (Grade 3) | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 2a | 14.6 percentage of participants |
| Arm 3: No Treatment Unless Severe (Grade 3) | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 2b | 4.9 percentage of participants |
| Arm 3: No Treatment Unless Severe (Grade 3) | Severity of Rash Caused by Erlotinib | Maximal Rash Grade 1 | 46.3 percentage of participants |
Comparison: Maximal Rash Grade 1p-value: 0.5097Chi-squared
Comparison: Maximal Rash Grade 2ap-value: 0.474Chi-squared
Comparison: Maximal Severity Grade 2bp-value: 0.2123Chi-squared
Comparison: Maximal Severity Grade 3p-value: 0.5004Chi-squared
Comparison: Maximal Severity Grade 1p-value: 0.9072Chi-squared
Comparison: Maximal Severity Grade 2ap-value: 0.0464Chi-squared
Comparison: Maximal Severity Grade 2bp-value: 0.6759Chi-squared
Comparison: Maximal Severity Grade 3p-value: 0.0065Chi-squared
Comparison: Maximal Severity Grade 1p-value: 0.5898Chi-squared
Comparison: Maximal Severity Grade 2ap-value: 0.1921Chi-squared
Comparison: Maximal Severity Grade 2bp-value: 0.0882Chi-squared
Comparison: Maximal Severity Grade 3p-value: 0.0344Chi-squared
Secondary
Time to First Presentation of Rash
Time frame: Up to onset of rash while on study treatment
Population: Subjects with maximum severity of rash of grade 1, 2a, 2b and 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Prophylactic Treatment | Time to First Presentation of Rash | 17.4 days | Standard Deviation 19.7 |
| Arm 2: Reactive Treatment | Time to First Presentation of Rash | 13.3 days | Standard Deviation 19 |
| Arm 3: No Treatment Unless Severe (Grade 3) | Time to First Presentation of Rash | 12.0 days | Standard Deviation 11.1 |
p-value: 0.0147Wilcoxon (Mann-Whitney)